Heterocyclic modulators of lipid synthesis

ABSTRACT

Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by disregulation of the fatty acid synthase function by modulating the function and/or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatitis C infection, cancer and metabolic disorders, such as non-alcoholic steatohepatitis (NASH).”

RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S.Provisional Application No. 62/574,497, filed Oct. 19, 2017; and U.S.application Ser. No. 15/349,960, filed on Nov. 11, 2016, which iscontinuation in part of U.S. application Ser. No. 14/874,961, filed onOct. 5, 2015, which is a continuation of U.S. application Ser. No.14/315,133, filed on Jun. 25, 2014, now abandoned, which is acontinuation of U.S. application Ser. No. 13/415,660, filed Mar. 8,2012, now U.S. Pat. No. 8,871,790, which claims the benefit of theearlier filed U.S. Provisional Application No. 61/450,561 filed on Mar.8, 2011, U.S. Provisional Application No. 61/508,611, filed on Jul. 16,2011, and U.S. Provisional Application 61/585,642, filed on Jan. 11,2012; is a continuation in part of U.S. application Ser. No. 15/201,824,filed on Jul. 5, 2016, which is a divisional of U.S. application Ser.No. 14/587,908, filed on Dec. 31, 2014, now U.S. Pat. No. 9,428,502,which is a continuation of PCT/US2013/048950, filed on Jul. 1, 2013,which claims the benefit of the earlier filed U.S. ProvisionalApplication No. 61/667,894, filed on Jul. 3, 2012, U.S. ProvisionalApplication No. 61/698,511, filed on Sep. 7, 2012, U.S. ProvisionalApplication 61/699,819, filed on Sep. 11, 2012. and U.S. ProvisionalApplication 61/785,933, filed on Mar. 14, 2013; and is a continuation inpart of U.S. application Ser. No. 15/110,154, filed on Jul. 7, 2016,which is a U.S. National Phase application, filed under 35 U.S.C. § 371,of PCT/US2015/010459, filed on Jan. 7, 2015, which claims the benefit ofthe earlier filed U.S. Provisional Application No. 61/924,520, filed onJan. 7, 2014.

The entire contents of each of these applications are incorporated byreference in their entireties for all purposes.

FIELD

The present disclosure relates generally to heterocyclic modulators oflipid synthesis and methods of use thereof. The present heterocyclicmodulators of lipid synthesis can be used for the treatment of disorderscharacterized by dysregulation in the fatty acid synthase function in asubject by modulating the fatty acid synthase pathway and/or the fattyacid synthase function.

BACKGROUND

Viral disease is a significant health concern that threatens largesegments of human populations. Some of the features related to viralinfection which are of concern to health care professionals include itshighly contagious nature (e.g., HIV, SARS, etc.) and high mutability.Some viruses are also oncogenic (such as HPV, EBV and HBV). Whileviruses are structurally amongst the simplest of organisms, they areregarded to be among the most difficult to control and present aformidable challenge for antiviral drug R&D.

Thus far, there have been a few antiviral drugs widely used in patients,such as Amantadine and Oseltamivir for influenza, Acyclovir forHSV-related infections, Ganciclovir for CMV infection, and multipleagents including co-formulated drugs (Efavirenz, emtricitabine, andtonfovir disoproxil fumarate) for AIDS treatments. These drugs possess avariety of undesirable neurological, metabolic and immunologicalside-effects. Therefore, development of new antiviral therapy has becomea major focus of medical and pharmaceutical research and development.

Infection by hepatitis C virus (HCV) is a serious health issue. It isestimated that 170 million people worldwide are chronically infectedwith HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liverfailure and hepatocellular carcinoma. Chronic HCV infection is thus amajor worldwide cause of liver-related premature mortality.

The present standard of care treatment regimen for HCV infectioninvolves combination therapy with interferon-alpha and ribavirin, oftenwith the addition of a direct-acting protease inhibitor (Telaprevir orBoceprevir). The treatment is cumbersome and sometimes has debilitatingand severe side effects. For this reason, many patients are not treatedin early stages of the disease. Additionally, some patient populationsdo not durably respond to treatment. New and effective methods oftreating HCV infection are urgently needed.

The dominant therapeutic approaches that are currently employed to treatcancer include surgical removal of primary tumors, tumor irradiation,and parenteral application of anti-mitotic cytotoxic agents.Unfortunately, only a relatively small cross-section of cancer patientshave tumors that are “addicted” to a specific pathway, and can thereforebe treated with newer targeted agents. The continued dominance of theselong established therapies is mirrored by the lack of improvement insurvival rates for most cancers. In addition to limited clinicalsuccess, devastating side effects accompany classic therapies. Bothradiation- and cytotoxic-based therapies result in the destruction ofrapidly dividing hematopoietic and intestinal epithelial cells leadingto compromised immune function, anemia, and impaired nutrientabsorption. Surgical intervention often results in a release of tumorcells into the circulation or lymph systems from which metastatic tumorscan subsequently be established. Improved methods for the treatment ofcancer are needed.

Non-alcoholic liver disease (NAFLD), a condition in which the livercontains more than 5% fat by weight and is not caused by alcoholconsumption, is a disease which currently affects ˜20-30% of the US andgeneral western world population, and is associated with a significantincreased risk of morbidity extending beyond the liver to cardiovasculardisease (i.e., carotid atherosclerotic plaques and endothelialdysfunction), chronic kidney disease and malignancy. Obesity andmetabolic syndrome are two key risk factors for NAFLD which arecharacterized as an imbalance in energy utilization and storage. Thisimbalance leads to dysregulated metabolic pathways and inflammatoryresponses that drive further changes leading to liver damage andcomorbid conditions. Along with the progression of metabolic syndrome,NAFLD leads to more advanced liver disease starting with non-alcoholicsteatohepatitis (NASH) which can then progress to significant liverdiseases including cirrhosis and hepatocellular carcinoma.

The synthesis of fatty acids in the liver, a pathway termed hepatic denovo lipogenesis (DNL), is increased in subjects with metabolic syndromeand NAFLD (Donnelly, K. L, et. al., “Sources of Fatty Acids Stored inLiver and Secreted via Lipoproteins in Patients with Nonalcoholic FattyLiver Disease,” J. Clin. Invest. 115 (5). 2005, 1343-51; Lambert, J. E,et. al., “Increased De Novo Lipogenesis Is a Distinct Characteristic ofIndividuals with Nonalcoholic Fatty Liver Disease,” Ygast 146 (3).2014,726-35). The DNL pathway not only produces fatty acids that contributeto elevated liver stores of triglycerides, but the fatty acids that areproduced are saturated fatty acid species, primarily palmitate, whichcontribute to signaling events that increase liver inflammation (Wei,Y., “Saturated Fatty Acids Induce Endoplasmic Reticulum Stress andApoptosis Independently of Ceramide in Liver Cells,” Am. J. Physio.Endocrinol. Metab. 291 (2): 2006. E275-81, Kakazu, E., et al.,“Hepatocytes Release Ceramide-rich Proinflammatory ExtracellularVesicles in an IRE1alpha dependent manner,” Abstract 58. AASLD—The LiverMeeting, San Francisco, Calif., USA, 13-17, Nov. 2015). One of the keyenzymes in the DNL pathway is fatty acid synthase (FASN) which is solelyresponsible for synthesizing palmitate. Thus, DNL is an importantpathway for therapeutic intervention to reduce the consequencesassociated with metabolic syndrome and NAFLD.

Inhibition of FASN has the potential to be a treatment for a wide rangeof diseases including cancer, viral disease, metabolic disease, NAFLD,NASH, and inflammatory diseases, (i.e., rheumatoid arthritis, gout,pulmonary fibrosis, COPD, IBD and transplant rejection). Additionally,FASN inhibition may provide therapeutic benefits in cardiovasculardisease, type II diabetes, and metabolic syndrome. Successful treatmentof these diseases is still a highly unmet need. While there aretreatments available for diabetes and cardiovascular disease, there arecurrently no drugs approved to treat metabolic syndrome, NAFLD, or NASH.Thus, there is a need for novel and potent small molecule inhibitors ofFASN for the treatment of these diseases.

SUMMARY

The present disclosure addresses the deficiencies for antiviral andanticancer treatments by providing novel heterocyclic modulators oflipid synthesis having improved antiviral and anticancer activities.

In various aspects, the present disclosure provides for compounds ofStructure (I):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is hydrogen orC₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or absent;

A is CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently hydrogen,C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, or alkylamino;

R₁₇ and R₁₈ are each independently hydrogen or alkyl or can optionallyjoin together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructure (II):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is hydrogen orC₁₋₆ alkyl and R′ is hydrogen C₁₋₆ alkyl, or absent;

L and D are each independently C or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy. C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently hydrogen,C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, or alkylamino;

R₁₇ and R₁₈ are each independently hydrogen or alkyl or can optionallyjoin together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructure (III):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is hydrogen orC₁₋₆ alkyl and R′ is hydrogen C₁₋₆ alkyl, or absent;

Q is C or N;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or if Q is Nthen R₃ is absent;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently hydrogen,C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,alkylamino —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, or alkylamino;

R₁₇ and R₁₈ are each independently hydrogen or alkyl or can optionallyjoin together to form a bond;

R₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclyl;

n is 0, 1, or 2; and

m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructures (IV-A), (IV-B), or (IV-C):

or a pharmaceutically acceptable salt thereof, wherein:

L₁, L₂, L₃, L₄, and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is absent if L₁is N, or R₂₃ and R₂₄ taken together with the atoms to which they areattached join together to form a heterocyclyl, heteroaryl, orcycloalkyl;

R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄ taken together withthe atoms to which they are attached join together to form aheterocyclyl, heteroaryl, or cycloalkyl;

R₂₆ is hydrogen, heteroaryl, heterocyclyl, —N(R₁₃)(R₁₄), or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In various aspects, the present disclosure provides for compounds ofStructure (V):

or a pharmaceutically acceptable salt thereof, wherein:

L₇ is N or O, wherein R₃₀ is absent if L₇ is O;

A is CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₂₉ and R₃₀ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,hydroxyalkyl, heteroaryl, heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆,—R₄₈C(═O)R₄₇, or R₂₉ and R₃₀ taken together with the atoms to which theyare attached join together to form a heteroaryl or heterocyclyl, whereinR₃₀ is absent if L₇ is O;

R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₄₈ is alkyl or is absent;

R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino; and

v is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructures (VI-A) or (VI-B):

or a pharmaceutically acceptable salt thereof, wherein:

L₁₃, L₁₄, L₁₅, and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF₃, —OCF₃,—S(═O)₂R₂₀, or —N(R₁₅R₁₆);

R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆), heterocyclyl, orheteroaryl;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In various aspects, the present disclosure provides for compounds ofStructure (VI-J):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R₃₅₁ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl.

In some aspects of Structure (VI-J), R³ is H or halogen.

In some aspects of Structure (VI-J), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (VI-J), R²² is C₁-C₂ alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl.

In some aspects of Structure (VI-J), R³ is H or F.

In some aspects of Structure (VI-J), R¹ is —CN.

In some aspects of Structure (VI-J), R¹ is —CF₃.

In some aspects of Structure (VI-J), R²² is H, methyl or ethyl.

In some aspects of Structure (VI-J), R²² is H.

In some aspects of Structure (VI-J), R²² is methyl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—NHR³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is(R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is hydrogen, R³is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—NHR³⁵¹ whereR³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or(S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—O—R³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—O—R³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is (R)-3-tetrahydrofuranyl or(S)-3-tetrahydrofuranyl.

In some aspects of Structure (VI-J), compounds have a structure selectedfrom the group consisting of:

In various aspects, the present disclosure provides for compounds ofStructures (VII-A) or (VII-B):

or a pharmaceutically acceptable salt thereof, wherein:

L₁₆ is C or N, wherein R₄₁ is absent if L₁₆ is N;

L₁₇, L₁₈, and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₄₀, R₄₂, and R₄₃ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆alkoxy, —S(═O)₂R₂₀, —C(═O)R, hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), or R₄₁and R₄₂ taken together with the atoms to which they are attached jointogether to form a heteroaryl or heterocyclyl;

R₄₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R,hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), R₄₁ is absent if L₁₆ is N, or R₄₁and R₄₂ taken together with the atoms to which they are attached jointogether to form a heteroaryl or heterocyclyl;

R is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In various aspects, the present disclosure provides for compounds ofStructures (VIII-A), (VIII-B), or (VIII-C):

or a pharmaceutically acceptable salt thereof, wherein:

L₁₉ and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₄₄ and R₄₅ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,—S(═O)₂R₂₀, —C(═O)R, or —N(R₁₃R₁₄); and

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In various aspects, compounds of Structure (IX) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R₂₄ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)—OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl.

In some aspects of Structure (IX), R²⁴ is C₁-C₄ straight or branchedalkyl or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) whereint is 0 or 1.

In some aspects of Structure (IX), R²¹ is halogen, C₁-C₄ straight orbranched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom, —S(O)_(u)—(C₁-C₄ straight orbranched alkyl) wherein u is 0 or 2, or —S(O)_(u)—(C₃-C₅ cycloalkyl)wherein u is 0 or 2;

In some aspects of Structure (IX), R³ is H or halogen.

In some aspects of Structure (IX), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (IX), both L¹ and L² are N.

In some aspects of Structure (IX), R²¹ is C₁-C₂ alkyl or C₃-C₅cycloalkyl and R²² is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (IX), R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂alkyl) wherein t is 0 or 1.

In some aspects of Structure (IX), R²¹ is C₃-C₅ cycloalkyl, R²² is C₁-C₂alkyl and R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl, R²² is C₁-C₂ alkyland R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl.

In some aspects of Structure (IX), R³ is H or F.

In some aspects of Structure (IX), R¹ is —CN.

In some aspects of Structure (IX), R¹ is —CF₃.

In some aspects of Structure (IX), R²² is H, methyl or ethyl.

In some aspects of Structure (IX), R²² is H.

In some aspects of Structure (IX), R²² is methyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethoxy or ethoxy.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is CH, L² is N, and R²⁴ ismethyl, ethyl, hydroxy methyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L² is CH, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), compounds have a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (X) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not —CN or halogen, it is optionally substituted with one ormore halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ and two R⁶⁰¹.

In some aspects of Structure (X), R²¹ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl.

In some aspects of Structure (X), R³ is H or halogen.

In some aspects of Structure (X), R¹ is —CN or C₁-C₂ haloalkyl.

In some aspects of Structure (X), R³ is H or F.

In some aspects of Structure (X), R¹ is —CN.

In some aspects of Structure (X), R¹ is —CF₃.

In some aspects of Structure (X), n is 1.

In some aspects of Structure (X), n is 2.

In some aspects of Structure (X), m is 1

In some aspects of Structure (X), m is 2.

In some aspects of Structure (X), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some aspects of Structure (X), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂.

In some aspects of Structure (X), n is 2, m is 1, L³ is —N—C(O)—O—(C₁-C₂alkyl).

In some aspects of Structure (X), L³ is NR⁵⁰, R⁵⁰ is C₁-C₂ alkyl; R²¹ iscyclobutyl; R²² is H or methyl; R³ is H; R¹ is —CN; m is 2 and n is 1 or2.

In some aspects of Structure (X), n is 2, m is 1, L³ is O and s is O.

In some aspects of Structure (X), R²² is H, methyl or ethyl.

In some aspects of Structure (X), R²² is methyl.

In some aspects of Structure (X), R²² is H.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is NR⁵⁰ where R⁵⁰is methyl or ethyl.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is O.

In some aspects of Structure (X), the compound has a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (XI) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₁ alkyl).

In some aspects of Structure (XI), R³ is H or halogen.

In some aspects of Structure (XI), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (XI), R²¹ is C₃-C₄ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl.

In some aspects of Structure (XI), R³ is H or F.

In some aspects of Structure (XI), R¹ is —CN.

In some aspects of Structure (XI), R¹ is —CF₃.

In some aspects of Structure (XI), R²² is H, methyl or ethyl.

In some aspects of Structure (XI), R²² is H.

In some aspects of Structure (XI), R²² is methyl.

In some aspects of Structure (XI), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl or ethyl.

In some aspects of Structure (XI), the compound has a structure selectedfrom the group consisting of:

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Structures (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) and apharmaceutically acceptable carrier, excipient, or diluent.

In various aspects, the present disclosure provides methods of treatinga condition characterized by disregulation of a fatty acid synthasefunction in subject, the method comprising administering to the subjectin need of such treatment an effective amount of a compound of any oneof the Structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X) or (XI). In various aspects the condition characterized bydisregulation of the fatty acid synthase function is a viral infectionor cancer. In various aspects the viral infection is treated using acompound of any one of the Structures (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X) or (XI) in combination with one or moreadditional antiviral treatments. In various aspects the cancer istreated using a compound of any one of the Structures (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combination withone or more additional cancer treatments. In various aspects, the viralinfection is hepatitis C.

In various aspects, the present disclosure relates to a method oftreating fatty liver disease in a subject in need thereof, the methodcomprising administering to the subject in need thereof a fatty acidsynthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom,

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R₂₆, twoR⁶⁰, two R⁵⁰, two R⁵⁰² or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)-O-R³⁵³ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R¹¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F:

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)—O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F:

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R₂₄ is C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂;—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰ —, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R₂ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R₂₁ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R₂ is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R² isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating non-alcoholic steatohepatitis (NASH) in a subject in needthereof, the method comprising administering to the subject in needthereof a fatty acid synthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R² is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁶—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating non-alcoholic fatty liver disease (NAFLD) in a subject in needthereof, the method comprising administering to the subject in needthereof a fatty acid synthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)-13 O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, two R⁶⁰,two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R² is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)—N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating metabolic syndrome in a subject in need thereof, the methodcomprising administering to the subject in need thereof a fatty acidsynthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R₂₁ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁶—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O-(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating liver cirrhosis in a subject in need thereof, the methodcomprising administering to the subject in need thereof a fatty acidsynthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O-(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O-(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(i) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating liver fibrosis in a subject in need thereof, the methodcomprising administering to the subject in need thereof a fatty acidsynthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(i) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating liver cancer in a subject in need thereof, the methodcomprising administering to the subject in need thereof a fatty acidsynthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(i) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating a disease or condition in which interleukin 1 beta (IL1β)levels are elevated in a subject in need thereof, the method comprisingadministering to the subject in need thereof a fatty acid synthaseinhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R₂₄₁ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R₂ is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₁ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating a disease or condition in which t-helper (T_(h)) cell levelsare elevated in a subject in need thereof, the method comprisingadministering to the subject in need thereof a fatty acid synthaseinhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R₂ is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), alkyl)_(t)-O—(C₁-C₄straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄ alkyl), or—C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R₂₄₁ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R₂ is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating a disease or condition in which regulatory t cells (T_(reg))are reduced or suppressed in a subject in need thereof, the methodcomprising administering to the subject in need thereof a fatty acidsynthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R₂ is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)h-OH, —(C₁-C₄alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R₂ is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method ofreversing established non-alcoholic steatohepatitis (NASH), the methodcomprising administering to a subject in need thereof a fatty acidsynthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,—C₁-C₄ straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₄ alkyl;

each R²⁶ is independently —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R² is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R³⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(i) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method ofreducing fibrotic gene expression, the method comprising administeringto a subject in need thereof a fatty acid synthase inhibitor having aformula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R² is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₁-C₆ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, the present disclosure relates to a method oftreating skin fibrosis, the method comprising administering to a subjectin need thereof a fatty acid synthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or

(c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R₂₁ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R² is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl;

R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; and

R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:

each t is independently 0 or 1; and

each R²⁴¹ is independently H or C₁-C₂ alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, whereinR⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen, or C₁-C₂ alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl; and

R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R²⁴¹ is H or C₁-C₂ alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen, or C₁-C₂ alkyl; and

R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ isC₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered heterocycle, aryl orheteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR²⁶— with the proviso thatnot more than 2 of W, X, Y and Z are —N—;

each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —N(R²⁷)₂,—S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);

each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄ alkyland join to form a 3- to 6-membered ring together with the N to whichthey are attached and wherein the ring optionally includes one oxygenatom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CNor halogen, R¹ is optionally substituted with one or more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R¹¹ is H or —CH₃;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and

R²² is H, halogen or C₁-C₂ alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;

each R² is independently hydrogen, halogen or C₁-C₄ alkyl;

R³ is H or F;

R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle;

R²² is H, halogen or C₁-C₂ alkyl;

R²⁴ is —O—(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R²⁴ isoptionally substituted with one or more hydroxyl or halogen; and

R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, wherein R²⁵ isoptionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating non-alcoholicsteatohepatitis (NASH) or symptoms of NASH. In further aspects,compounds having Structure (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI) or as provided in Table 1 can be used fortreating non-alcoholic steatohepatitis (NASH) or symptoms of NASH.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating non-alcoholicfatty liver disease (NAFLD). In further aspects, compounds havingStructure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1 can be used for treating non-alcoholicfatty liver disease (NAFLD).

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating metabolicsyndrome. In further aspects, compounds having Structure (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided inTable 1 can be used for treating metabolic syndrome.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating livercirrhosis. In further aspects, compounds having Structure (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided inTable 1 can be used for treating liver cirrhosis.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating liver fibrosis.In further aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for treating liver fibrosis.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating liver cancer.In further aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for treating liver cancer.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating liver fibrosis.In further aspects, compounds having Structure (I, (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for treating liver fibrosis.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating a disease orcondition in which interleukin 1 beta (IL1β) levels are elevated. Infurther aspects, compounds having Structure (I), (II), (III), (IV), (V),(VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can beused for treating a disease or condition in which interleukin 1 beta(IL1β) levels are elevated.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating a disease orcondition in which t-helper (T_(h)) cell levels are elevated. In furtheraspects, compounds having Structure (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used fortreating a disease or condition in which t-helper (T_(h)) cell levelsare elevated.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating a disease orcondition in which regulatory t cells (T_(reg)) are reduced orsuppressed. In further aspects, compounds having Structure (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided inTable 1 can be used for a disease or condition in which regulatory tcells (Treg) are reduced or suppressed.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating or reversingestablished non-alcoholic steatohepatitis (NASH). In further aspects,compounds having Structure (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI) or as provided in Table 1 can be used fortreating or reversing established non-alcoholic steatohepatitis (NASH).

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for reducing fibrotic geneexpression. In further aspects, compounds having Structure (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided inTable 1 can be used for reducing fibrotic gene expression.

In various aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for the manufacture of a medicament for treating skin fibrosis.In further aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for treating skin fibrosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a correlation between FASN inhibition and HCVinhibition.

FIG. 2 shows images of liver tissue samples stained with Oil red O orMasson's taken from C57BL/6NCrSim mice treated with vehicle or 10 mg/kgof Compound 364A. The results show that treatment with FASN inhibitorCompound 364A inhibited the development of steatosis.

FIG. 3 shows images of liver tissue samples stained with Oil red O takenfrom C57BL/6J mice treated with vehicle for 28 days, vehicle for 57 daysor vehicle for 28 days followed by 10 mg/kg Compound 364A for 29 days.The results show that treatment with FASN inhibitor Compound 364Ainhibited the development of hepatic steatosis.

FIG. 4 is a graph showing IL-1β levels in untreated rats and in ratstreated with vehicle, 60 mg/kg of Compound 6B, or 100 mg/kg of Compound6B. The results show that treatment with Compound 6B lowered IL-1β betalevels in blood serum after feeding fasted rats.

FIG. 5 is a graph showing IL-1β levels in rats treated with vehicle, 60mg/kg of Compound 6B, or 100 mg/kg of Compound 6B. The results show thattreatment with Compound 6B lowered IL-1β beta levels in blood serum 22hours after feeding fasted rats.

FIG. 6A is a graph showing IL-1β levels in mice fed a high fat diet for14 days and then treated with vehicle, 3 mg/kg of Compound 364A, or 10mg/kg of Compound 364A. FIG. 6B is a graph showing IL1β levels in micefed a high fat diet for 37 days and then treated with vehicle, 3 mg/kgof Compound 364A, or 10 mg/kg of Compound 364A. Mice treated withCompound 364A had reduced levels of IL-1 beta at both 14 and 37 days,both before reintroduction of food and after feeding, compared to micewhich received vehicle.

FIG. 7A is a graph showing secretion of IL-1β levels from human PBMCwithout stimulation or after 24 hours of stimulation withlipopolysaccharide (LPS) or lipoteichoic acid (LTA) when treated withvehicle or with 10 μM of Compound 242A. FIG. 7B is a graph showingsecretion of IL-1β levels from human monocytes without stimulation orafter 24 hours of stimulation with lipopolysaccharide (LPS) orlipoteichoic acid (LTA) when treated with vehicle or with 10 μM ofCompound 242A. For monocytes, Compound 242A treatment reduced the levelof IL-1 beta resulting from LTA stimulation whereas only a slightreduction was observed after LPS stimulation. For PBMC, Compound 242Atreatment reduced the level of IL-1 beta resulting from both LTA and LPSstimulation.

FIGS. 8A and 8B are plots showing the results of flow cytometry analysisof mouse T cells treated with vehicle (DMSO) or 50 nM of Compound 364A.FASN inhibition of mouse CD4+ naive T cells with 4 days of Th₁₇differentiation conditions inhibits Th₁₇ cell differentiation andstimulates T_(reg) differentiation.

FIGS. 9A and 9B are plots showing the results of flow cytometry analysisof human T cells from Donor 1 treated with vehicle (DMSO) or 50 nM ofCompound 364A. FIGS. 9C and 9D are plots showing the results of flowcytometry analysis of human T cells from Donor 2 treated with vehicle(DMSO) or 50 nM of Compound 364A. FASN inhibition with Compound 364A ofhuman CD4+ naive T cells from two different donors with 4 days of Th₁₇differentiation conditions inhibits TH₁₇ cell differentiation andstimulates T_(reg) differentiation.

FIGS. 10A and 10B are plots showing the results of flow cytometryanalysis of human T cells from Donor 1 treated with vehicle (DMSO) or 50nM of Compound 152. FIGS. 10C and 10D are plots showing the results offlow cytometry analysis of human T cells from Donor 2 treated withvehicle (DMSO) or 50 nM of Compound 152. FASN inhibition with Compound152 of human CD4+ naive T cells from two different donors with 4 days ofTh₁₇ differentiation conditions inhibits TH₁₇ cell differentiation andstimulates T_(reg) differentiation.

FIG. 11 is a schematic of the study design and dose groups for Compound364A and pirfenidone in Example 10.

FIG. 12A is a plot of plasma alanine aminotransferase (ALT) as afunction of treatment with Compound 364A and/or pirfenidone. FIG. 12B isa plot of plasma aspartate aminotransferase (AST) as a function oftreatment with Compound 364A and/or pirfenidone. FIG. 12C is a plot ofplasma total cholesterol (TC) as a function of treatment with Compound364A and/or pirfenidone.

FIG. 13A is a plot of liver triglycerides as a function of treatmentwith Compound 364A and/or pirfenidone. FIG. 13B is a plot of livercholesterol as a function of treatment with Compound 364A and/orpirfenidone.

FIG. 14A is a plot of the change in liver steatosis after dosing withvehicle (control). FIG. 14B is a plot of the change in liver steatosisafter dosing with Compound 364A. FIG. 14C is a plot of the change inliver steatosis after dosing with pirfenidone. FIG. 14D is a plot of thechange in liver steatosis after dosing with Compound 364A andpirfenidone.

FIG. 15A is a plot of the change in liver inflammation after dosing withvehicle (control). FIG. 15B is a plot of the change in liverinflammation after dosing with Compound 364A. FIG. 15C is a plot of thechange in liver inflammation after dosing with pirfenidone. FIG. 15D isa plot of the change in liver inflammation after dosing with Compound364A and pirfenidone.

FIG. 16A is a plot of the change in liver ballooning after dosing withvehicle (control). FIG. 16B is a plot of the change in liver ballooningafter dosing with Compound 364A. FIG. 16C is a plot of the change inliver ballooning after dosing with pirfenidone. FIG. 16D is a plot ofthe change in liver ballooning after dosing with Compound 364A andpirfenidone.

FIG. 17A is a plot of the change in liver fibrosis after dosing withvehicle (control). FIG. 17B is a plot of the change in liver fibrosisafter dosing with Compound 364A. FIG. 17C is a plot of the change inliver fibrosis after dosing with pirfenidone. FIG. 17D is a plot of thechange in liver fibrosis after dosing with Compound 364A andpirfenidone.

FIG. 18A is a plot of the change in liver NAFLD activity score (NAS)after dosing with vehicle (control). FIG. 18B is a plot of the change inliver NAFLD activity score (NAS) after dosing with Compound 364A. FIG.18C is a plot of the change in liver NAFLD activity score (NAS) afterdosing with pirfenidone. FIG. 18D is a plot of the change in liver NAFLDactivity score (NAS) after dosing with Compound 364A and pirfenidone.

FIG. 19 is a plot of the change in liver collagen gene expression afterdosing with vehicle (control), Compound 364A, pirfenidone, or Compound364A and pirfenidone.

FIG. 20 is a 2-D plot of the change in liver collagen gene expression bygene analysis of liver biopsies after dosing with vehicle (control),Compound 364A, pirfenidone, or Compound 364A and pirfenidone.

FIG. 21 is a schematic of the study design and dose groups in Example11.

FIG. 22 is a plot of the change in skin collagen content in the mice asa function of the dose of Compound 364A in Example 11.

FIG. 23 shows the relative mRNA expression of fibrotic genes inimmortalized human hepatic stellate cells (LX-2 cells) after treatmentwith Compound 364A or sorafenib. FIG. 23A is a plot of the mRNAexpression of Col 1a1. FIG. 23B is a plot of the mRNA expression ofαSMA. FIG. 23C is a plot of the mRNA expression of βPDGFR. FIG. 23D is aplot of the mRNA expression of TGFbR1. FIG. 23E is a plot of the mRNAexpression of TIMP1. FIG. 23F is a plot of the mRNA expression of TIMP2.FIG. 23G is a plot of the mRNA expression of MMP2.

DETAILED DESCRIPTION

The present disclosure addresses the deficiencies in treating conditionscharacterized by disregulation of the FASN function in a subject, suchas viral infection, cancer and metabolic disorders, by providing novelheterocyclic modulators of lipid synthesis.

In certain aspects, the present disclosure provides compositions andmethods for treatment of viral infections. In general, the compositionsand methods for treatment of viral infections are directed towardmodulation of the fatty acid synthesis pathway. The fatty acid synthesispathway is involved in the replication of viruses into the host cells.The present invention embodies methods for the treatment of viralinfection, such as hepatitis C infections, yellow fever infections, andhuman rhinovirus infections, or any virus that targets the fatty acidsynthesis pathway.

In certain aspects, the present disclosure provides compositions andmethods for the treatment of cancer. Fatty acid synthase is responsiblefor conversion of malonyl-CoA into long-chain fatty acids, which is anearly reaction in fatty acid biosynthesis. Fatty acid synthase isoverexpressed in many cancer cells. Without being bound by anyparticular theory, it is hypothesized that inhibition of fatty acidsynthase expression or fatty acid synthase activity selectivitysuppresses proliferation and induces cell death of cancer cells, withlittle toxicity towards normal cells.

Further, the present disclosure provides compounds and methods formodulating host cell targets that are targeted by viruses. Suchmodulation of host cell targets can include either activation orinhibition of the host cell targets. Accordingly, compounds thatmodulate, e.g., inhibit, the activity of a non-viral protein, e.g., ahost cell protein, e.g., components of the fatty acid synthesis pathway,can be used as antiviral pharmaceutical agents.

Definitions

Chemical moieties referred to as univalent chemical moieties (e.g.,alkyl, aryl, etc.) also encompass structurally permissible multivalentmoieties, as understood by those skilled in the art. For example, whilean “alkyl” moiety generally refers to a monovalent radical (e.g.,CH₃Cl₂—), in appropriate circumstances an “alkyl” moiety can also referto a divalent radical (e.g., —CH₂CH₂—, which is equivalent to an“alkylene” group). Similarly, under circumstances where a divalentmoiety is required, those skilled in the art will understand that theterm “aryl” refers to the corresponding divalent arylene group.

All atoms are understood to have their normal number of valences forbond formation (e.g., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the atom's oxidation state). On occasion a moiety can bedefined, for example, as (A)_(a)B, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B and when a is 1 the moiety is AB.

Where a substituent can vary in the number of atoms or groups of thesame kind (e.g., alkyl groups can be C₁, C₂, C₃, etc.), the number ofrepeated atoms or groups can be represented by a range (e.g., C₁-C₆alkyl) which includes each and every number in the range and any and allsub ranges. For example, C₁-C₃ alkyl includes C₁, C₂, C₃, C₁₋₂, C₁₋₃,and C₂₋₃ alkyl.

“Alkanoyl” refers to a carbonyl group with a lower alkyl group as asubstituent.

“Alkylamino” refers to an amino group substituted by an alkyl group.

“Alkoxy” refers to an O-atom substituted by an alkyl group as definedherein, for example, methoxy [OCH₃, a C₁alkoxy]. The term “C₁₋₆ alkoxy”encompasses C₁ alkoxy, C₂ alkoxy, C₃ alkoxy, C₄ alkoxy, C₅ alkoxy, C₆alkoxy, and any sub-range thereof.

“Alkoxycarbonyl” refers to a carbonyl group with an alkoxy group as asubstituent.

“Alkyl,” “alkenyl,” and “alkynyl,” refer to optionally substituted,straight and branched chain aliphatic groups having from 1 to 30 carbonatoms, or preferably from 1 to 15 carbon atoms, or more preferably fromI to 6 carbon atoms. Examples of alkyl groups include, withoutlimitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, andpropynyl. The term “heteroalkyl” as used herein contemplates an alkylwith one or more heteroatoms.

“Alkylene” refers to an optionally substituted divalent radical which isa branched or unbranched hydrocarbon fragment containing the specifiednumber of carbon atoms, and having two points of attachment. An exampleis propylene [—CH₂CH₂CH₂—, a C₃alkylene].

“Amino” refers to the group —NH₂.

“Aryl” refers to optionally substituted aromatic groups which have atleast one ring having a conjugated pi electron system and includescarbocyclic aryl, and biaryl groups, all of which can be optionallysubstituted. Phenyl and naphthyl groups are preferred carbocyclic arylgroups.

“Aralkyl” or “arylalkyl” refer to alkyl-substituted aryl groups.Examples of aralkyl groups include butylphenyl, propylphenyl,ethylphenyl, methylphenyl, 3,5-dimethylphenyl, tert-butylphenyl.

“Carbamoyl” as used herein contemplates a group of the structure

where in R^(N) is selected from the group consisting of hydrogen, —OH,C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.

“Carbonyl” refers to a group of the structure

“Cycloalkyl” refers to an optionally substituted ring, which can besaturated or unsaturated and monocyclic, bicyclic, or tricyclic formedentirely from carbon atoms. An example of a cycloalkyl group is thecyclopentenyl group (C₅H₇—), which is a five carbon (C₅) unsaturatedcycloalkyl group.

“Heterocycle” refers to an optionally substituted 5- to 7-memberedcycloalkyl ring system containing 1, 2 or 3 heteroatoms, which can bethe same or different, selected from N, O or S, and optionallycontaining one double bond.

“Halogen” refers to a chloro, bromo, fluoro or iodo atom radical. Theterm “halogen” also contemplates terms “halo” or “halide.”

“Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen,sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygenand sulfur being particularly preferred heteroatoms in the compounds ofthe present disclosure.

“Heteroaryl” refers to optionally substituted aryl groups having from 1to 9 carbon atoms and the remainder of the atoms are heteroatoms, andincludes those heterocyclic systems described in “Handbook of Chemistryand Physics,” 49th edition, 1968, R. C. Weast, editor, The ChemicalRubber Co., Cleveland, Ohio. See particularly Section C, Rules forNaming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitableheteroaryls include thienyl, pyrrolyl, furyl, pyridyl, pyrimidyl,pyrazinyl, pyrazotyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl,pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl isoquinolylindazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl,benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl,benzothiadiazolyl, and the like.

An “optionally substituted” moiety can be substituted with from one tofour, or preferably from one to three, or more preferably one or twonon-hydrogen substituents. Unless otherwise specified, when thesubstituent is on a carbon, it is selected from the group consisting of—OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, none of which are further substituted. Unlessotherwise specified, when the substituent is on a nitrogen, it isselected from the group consisting of C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamidenone of which are further substituted.

The term “sulfonamide” as used herein contemplates a group having thestructure

wherein R^(N) is selected from the group consisting of hydrogen, —OH, C₁to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

The term “sulfonate” as used herein contemplates a group having thestructure

wherein R^(s) is selected from the group consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, alkynyl, alkanoyl, or C₁-C₁₀ alkoxycarbonyl.

“Sulfonyl” as used herein alone or as part of another group, refers toan SO₂ group. The SO₂ moiety is optionally substituted.

Compounds of the present disclosure can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S) depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30, herebyincorporated by reference. The present disclosure contemplates variousstereoisomers and mixtures thereof and are specifically included withinthe scope of the present disclosure. Stereoisomers include enantiomers,diastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of the present disclosure can be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Also, moieties disclosed herein which exist in multiple tautomeric formsinclude all such forms encompassed by a given tautomeric structure.

Individual atoms in the disclosed compounds may be any isotope of thatelement. For example hydrogen may be in the form of deuterium.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans. It can be material which isnot biologically or otherwise undesirable, i.e., the material can beadministered to an individual without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include, forexample, acid addition salts and base addition salts.

“Acid addition salts” according to the present disclosure, are formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

“Base addition salts” according to the present disclosure are formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like. Acceptable inorganicbases include aluminum hydroxide, calcium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydroxide, and the like. It shouldbe understood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature can cause asingle crystal form to dominate.

The term “treating” includes the administration of the compounds oragents of the present invention to a subject to prevent or delay, toalleviate, or to arrest or inhibit development of the symptoms orconditions associated with fatty acid synthase-associated disorders,e.g., tumor growth associated with cancer. A skilled medicalpractitioner will know how to use standard methods to determine whethera patient is suffering from a disease associated with activity of fattyacid synthase, e.g., by examining the patient and determining whetherthe patient is suffering from a disease known to be associated withfatty acid synthase activity or by assaying for fatty acid synthaselevels in blood plasma or tissue of the individual suspected ofsuffering from fatty acid synthase associated disease and comparingfatty acid synthase levels in the blood plasma or tissue of theindividual suspected of suffering from a fatty acid synthase associateddisease with fatty acid synthase levels in the blood plasma or tissue ofa healthy individual. Increased securin levels are indicative ofdisease. Accordingly, the present invention provides, inter alia,methods of administering a compound of the present invention to asubject and determining fatty acid synthase activity in the subject.Fatty acid synthase activity in the subject can be determined beforeand/or after administration of the compound.

A “therapeutically effective amount” or “pharmaceutically effectiveamount” means the amount that, when administered to a subject, produceseffects for which it is administered. For example, a “therapeuticallyeffective amount,” when administered to a subject to inhibit fatty acidsynthase activity, is sufficient to inhibit fatty acid synthaseactivity. A “therapeutically effective amount,” when administered to asubject for treating a disease, is sufficient to effect treatment forthat disease,

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryaspect of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat are associated with the targeted or suspected disease or condition.These and other routine methods allow the clinician to select patientsin need of therapy using the methods and formulations of the presentinvention.

FASN Pathway Modulators

One aspect of the present disclosure includes a method of inhibitingviral infection or treating cancer by contacting a cell with an agentthat modulates the fatty acid synthesis pathway. This method ofinhibiting viral infection or treating cancer can be performed in vitroby contacting virally infected/cancerous cells with an agent thatmodulates the fatty acid synthesis pathway, or in vivo by administeringan agent that modulates the fatty acid synthesis pathway to a subjectinfected with a virus/having cancer. In one aspect, an agent can be aninhibitor of the fatty acid synthesis pathway.

Examples of inhibitors of the fatty acid synthesis pathway that can beused in the methods and compositions of the present disclosure aredescribed below.

Compounds of Structure (I)

In various aspects, the present disclosure provides for compounds ofStructure (I):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is hydrogen orC₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or absent;

A is CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently hydrogen,C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, or alkylamino;

R₁₇ and R₁₈ are each independently hydrogen or alkyl or can optionallyjoin together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In certain aspects of Structure (I), R₃ is F.

In certain aspects of Structure (I), A is CH.

In certain aspects of Structure (I), A is N.

In certain aspects of Structure (I), X, Y, and Z are NR′.

In certain aspects of Structure (I), R₄ is heteroaryl, heterocyclyl,—C(═O)N(R₅R₆), —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₄and R₁₁ taken together with the atoms to which they are attached jointogether to form a heteroaryl.

In certain aspects of Structure (I), R₅ is hydrogen and R₆ is aryl orheteroaryl.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is hydrogen orC₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or absent;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently hydrogen,C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, or alkylamino; and

R₁₇ and R₁₈ are each independently hydrogen or alkyl or can optionallyjoin together to form a bond

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-C) or (I-D):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is hydrogen orC₁₋₆ alkyl and R′ is hydrogen. C₁₋₆ alkyl, or absent;

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O),—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R₁₅R₁₆);and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-E), (I-F), (I-G), (I-H):

or a pharmaceutically acceptable salt thereof, wherein:

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or—N(R₁₅R₁₆); and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-I), (I-J), or (I-K):

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are each independently CR or NR′, wherein R is H or C₁₋₆ alkyland R′ is H, C₁₋₆ alkyl, or absent;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, or —S(═O)₂R₂₀;

R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R₁₅R₁₆);and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-L) or (I-M):

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are each independently CR or NR′, wherein R is H or C₁₋₆ alkyland R′ is H, C₁₋₆ alkyl, or absent;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R₁₅R₁₆);and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-N) or (I-O):

or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Structure (I) have the followingStructure (I-P):

or a pharmaceutically acceptable salt thereof, wherein:

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or—N(R₁₅R₁₆); and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-Q) (I-R), or (I-S):

or a pharmaceutically acceptable salt thereof,

In certain aspects, the compounds of Structure (I) have the followingStructure (I-T):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is H or C₁₋₆alkyl and R′ is H, C₁₋₆ alkyl, or absent;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O),—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or—N(R₁₅R₁₆); and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have the followingStructure (I-U):

or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-V):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is H or C₁₋₆alkyl and R′ is H, C₁₋₆ alkyl, or absent;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or—N(R₁₅R₁₆); and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compound of Structure (I) has the followingStructure (I-W):

or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-X), (I-Y), (I-Z), (I-AA), (I-AB), (I-AC),(I-AD), (I-AF), (I-AG), or (I-AH):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (II)

In various aspects, the present disclosure provides for compounds ofStructure (II):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is H or C₁₋₆alkyl and R′ is H, C₁₋₆ alkyl, or absent;

L and D are each independently C or N;

R is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or—N(R₁₅R₁₆);

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino;

R₁₇ and R₁₈ are each independently hydrogen or alkyl or can optionallyjoin together to form a bond;

n is 1 or 2; and

m is 0 or 1.

In certain aspects, the compounds of Structure (II) have the followingStructure (II-A):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is H or C₁₋₆alkyl and R′ is H, C₁₋₆ alkyl, or absent;

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or—N(R₁₅R₁₆); and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (II) have the followingStructure (II-B):

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are each independently CR or NR′, wherein R is H or C₁₋₆ alkyland R′ is H, C₁₋₆ alkyl, or absent;

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R₁₅R₁₆);and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (II) have one of thefollowing Structures (II-C), (II-D), or (II-E):

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are each independently CR or NR′, wherein R is H or C₁₋₅ alkyland R′ is H, C₁₋₆ alkyl, or absent;

R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃ takentogether with the atoms to which they are attached form a 5-memberedheterocyclyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂ and R₃taken together with the atoms to which they are attached form a5-membered heterocyclyl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, or —S(═O)₂R₂₀;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R₁₅R₁₆);and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compound of Structure (II) has the followingStructure (II-F):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (III)

In various aspects, the present disclosure provides for compounds ofStructure (III):

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and Z are each independently CR or NR′, wherein R is H or C₁₋₆alkyl and R′ is H, C₁₋₆ alkyl, or absent;

Q is C or N;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or if Q is N R₃is absent;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl, or R₁₁ and R₁₂taken together with the atoms to which they are attached join togetherto form a heteroaryl;

R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or—N(R₁₅R₁₆);

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino;

R₁₇ and R₁₈ are each independently hydrogen or alkyl or can optionallyjoin together to form a bond;

R₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclyl;

n is 0, 1, or 2; and

m is 0 or 1.

In certain aspects, the compounds of Structure (III) have one of thefollowing Structures (III-A), (III-B), or (III-C):

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are each independently CR or NR′, wherein R is H or C₁₋₆ alkyland R′ is H, alkyl, or absent;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈,—N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or R₄ and R₁₁ takentogether with the atoms to which they are attached join together to forma heteroaryl;

R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄), CF₃,—OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together with the atoms to whichthey are attached join together to form a heteroaryl;

R₅, R₆, R_(7,) R₈, R₉, and R₁₀ are each independently H, C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R₁₅R₁₆);and

R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (III) have one of thefollowing Structures (III-D), (III-E), or (III-F):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (IV)

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-A), (IV-B), or (IV-C):

or a pharmaceutically acceptable salt thereof, wherein:

L₁, L₂, L₃, L₄, and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is absent if L₁is N, or R₂₃ and R₂₄ taken together with the atoms to which they areattached join together to form a heterocyclyl, heteroaryl, orcycloalkyl;

R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄ taken together withthe atoms to which they are attached join together to form aheterocyclyl, heteroaryl, or cycloalkyl;

R₂₆ is hydrogen, heteroaryl, heterocyclyl, —N(R₁₃)(R₁₄), or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-D) and (IV-E):

or a pharmaceutically acceptable salt thereof.

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄),

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₂₆ is hydrogen, heteroaryl, heterocyclyl, —N(R₁₃)(R₁₄), or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-F) and (IV-G):

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;

s is 0, 1, or 2;

L₅ is CH₂, NH, S, or O;

L₆ is CH or N;

R₂₇ is hydrogen, —C(═O)R″, —S(═O)₂R₂₀;

R₂₈ is hydrogen, —C(═O)R″, —S(═O)₂R₂₀, or is absent if L₆ is O; and

R″ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄), or—N(R₁₃)(R₁₄).

In certain aspects of Structure (IV), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (IV), R₁ is cyano.

In certain aspects of Structure (IV), R₂ is hydrogen or halo; R₂ ishydrogen.

In certain aspects of Structure (IV), R₃ is hydrogen.

In certain aspects of Structure (IV), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (IV), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Structure (IV), R₂₅ is hydrogen.

In certain aspects of Structure (IV), L₂ is N.

In certain aspects of Structure (IV), L₁ is CH.

In certain aspects of Structure (IV), L₃ is CH.

In certain aspects of Structure (IV), L₄ is CH.

In certain aspects of Structure (IV), A is N.

In certain aspects of Structure (IV), A is CH.

In certain aspects of Structure (IV), R₂₆ is heterocyclyl.

In certain aspects of Structure (IV), R₂₄ is —N(R₁₃)(R₁₄).

In certain aspects of Structure (IV), L₅ and L₆ are each independentlyN. In certain aspects of Structure (IV), s is 1.

In certain aspects of Structure (IV), s is 0.

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-H), (IV-I), (IV-J), (IV-K), (IV-L), (IV-M),(IV-N), or (IV-O):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (V)

In various aspects, the present disclosure provides for compounds ofStructure (V):

or a pharmaceutically acceptable salt thereof, wherein:

L₇ is N or O, wherein R₃₀ is absent if L₇ is O;

A is CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₂₉ and R₃₀ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,hydroxyalkyl, heteroaryl, heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆,—R₄₈C(═O)R₄₇, or R₂₉ and R₃₀ taken together with the atoms to which theyare attached join together to form a heteroaryl or heterocyclyl, whereinR₃₀ is absent if L₇ is O;

R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₄₈ is alkyl or is absent;

R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino; and

v is 0 or 1.

In certain aspects, the compounds of Structure (V) have one of thefollowing Structures (V-A), (V-B), (V-C), or (V-D):

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₃₀ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyalkyl, heteroaryl,heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆, or —R₄₈C(═O)R₄₇, wherein R₃₀ isabsent if L₇ is O;

R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₄₈ is alkyl or is absent;

R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;

L₈, L₉, and L₁₀ are each independently CH₂, NH, or O;

L₁₁ and L₁₂ are each independently CH or N;

R₃₂ and R₃₃ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,—S(═O)₂R₂₀, —C(═O)R₄₆, hydroxyalkyl, hydroxyl, or are absent;

u is 0, 1, or 2; and

t is 0, 1, or 2.

In certain aspects of Structure (V), L₇ is N.

In certain aspects of Structure (V), L₇ is O.

In certain aspects of Structure (V), A is N.

In certain aspects of Structure (V), A is CH.

In certain aspects of Structure (V), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (V), R₁ is cyano.

In certain aspects of Structure (V), R₂ is hydrogen or halo.

In certain aspects of Structure (V), R₂ is hydrogen.

In certain aspects of Structure (V), R₃ is fluorine.

In certain aspects of Structure (V), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (V), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Structure (V), R₃₁ is hydrogen.

In certain aspects of Structure (V), R₃₀ is hydrogen.

In certain aspects of Structure (V), L₈ is O.

In certain aspects of Structure (V), L₉ is O.

In certain aspects of Structure (V), L₁₀ is O and L₁₁ is N.

In certain aspects of Structure (V), L₁₂ is N.

In certain aspects of Structure (V), R₃₂ and R₃₃ are each independentlyhydrogen.

In certain aspects, the compounds of Structure (V) have one of thefollowing Structures (V-I), (V-J), (V-K), (V-L), (V-M), (V-N), or (V-O):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (VI)

In certain aspects, the compounds of Structure (VI) have one of thefollowing Structures (VI-A) or (VI-B):

or a pharmaceutically acceptable salt thereof, wherein:

L₁₃, L₁₄, L₁₅, and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF₃, —OCF₃,—S(═O)₂R₂₀, or —N(R₁₅R₁₆);

R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆), heterocyclyl, orheteroaryl;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Structure (VI) have one of thefollowing Structures (VI-C) or (VI-D):

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆), heterocyclyl, orheteroaryl;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;and

R₃₇ and R₃₈ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,hydroxyalkyl, heteroaryl, heterocyclyl, or R₃₇ and R₃₈ taken togetherwith the atoms to which they are attached join together to form aheteroaryl or heterocyclyl.

In certain aspects of Structure (VI), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (VI), R₁ is cyano.

In certain aspects of Structure (VI), R₂ is hydrogen or halo.

In certain aspects of Structure (VI), R₂ is hydrogen.

In certain aspects of Structure (VI), R₃ is fluorine.

In certain aspects of Structure (VI), R₂₁ and 22 are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (VI), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Structure (VI), R₃₅ is hydrogen.

In certain aspects of Structure (VI), R₃₄ is heteroaryl;

In certain aspects of Structure (VI), R₃₄ is thienyl, pyrryl, furyl,pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl,imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl,pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,thiadiazolyl, benzothiazolyl, or benzothiadiazolyl.

In certain aspects of Structure (VI), L₁₃ is N.

In certain aspects of Structure (VI), L₁₄ and L₁₅ are each independentlyCH.

In certain aspects of Structure (VI), A is N.

In certain aspects of Structure (VI), A is CH.

In certain aspects, the compounds of Structure (VI) have one of thefollowing Structures (VI-E), (VI-F), (VI-G), (VI-H), or (VI-I):

or a pharmaceutically acceptable salt thereof.

In various aspects, the present disclosure provides for compounds ofStructure (VI-J):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O-(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, or C₁-C₂ alkyl;

R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and

R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl, heterocyclyl, arylor heteroaryl, each of which is optionally substituted.

In some aspects of Structure (VI-J), R₃ is H or halogen.

In some aspects of Structure (VI-J), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (VI-J), R²² is C₁-C₂ alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl.

In some aspects of Structure (VI-J), R³ is H or F.

In some aspects of Structure (VI-J), R¹ is —CN.

In some aspects of Structure (VI-J), R¹ is CF3.

In some aspects of Structure (VI-J), R²² is H, methyl or ethyl.

In some aspects of Structure (VI-J), R²² is H.

In some aspects of Structure (VI-J), R²² is methyl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—NHR³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is(R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—NHR³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—O—R³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—O—R³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is (R)-3-tetrahydrofuranyl or(S)-3-tetrahydrofuranyl.

In some aspects of Structure (VI-J), compounds have a structure selectedfrom the group consisting of:

Compounds of Structure (VII)

In certain aspects, the compounds of Structure (VII) have one of thefollowing Structures (VII-A) or (VII-B):

or a pharmaceutically acceptable salt thereof, wherein:

L₁₆ is C or N, wherein R₄₁ is absent if L₁₆ is N;

L₁₇, L₁₈, and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₄₀, R₄₂, and R₄₃ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆alkoxy, —S(═O)₂R₂₀, —C(═O)R, hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), or R₄₁and R₄₂ taken together with the atoms to which they are attached jointogether to form a heteroaryl or heterocyclyl;

R₄₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R,hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), R₄₁ is absent if L₁₆ is N, or R₄₁and R₄₂ taken together with the atoms to which they are attached jointogether to form a heteroaryl or heterocyclyl;

R is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;

R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In certain aspects of Structure (VII), R₁ is hydrogen, cyano, C₁₋₆alkyl, C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (VII), R₁ is cyano.

In certain aspects of Structure (VII), R₂ is hydrogen or halo.

In certain aspects of Structure (VII), R₂ is hydrogen.

In certain aspects of Structure (VII), R³ is hydrogen.

In certain aspects of Structure (VII), R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (VII), R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In certain aspects of Structure (VII), R₃₉ is hydrogen.

In certain aspects of Structure (VII), R₄₀ is hydrogen.

In certain aspects of Structure (VII), L₁₆ is N.

In certain aspects of Structure (VII), L₁₇ is N.

In certain aspects of Structure (VII), L₁₈ is CH.

In certain aspects of Structure (VII), L₁₈ is N.

In certain aspects of Structure (VII), A is N.

In certain aspects of Structure (VII), A is CH.

In certain aspects of Structure (VII), R₄₂ is C₁₋₆ alkyl.

In certain aspects of Structure (VII), R₄₁ is C₁₋₆ alkyl.

In certain aspects, the compounds of Structure (VII) have one of thefollowing Structures (VII-C) or (VII-D):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (VIII)

In certain aspects, the compounds of Structure (VIII) have one of thefollowing Structures (VIII-A), (VIII-B), or (VIII-C):

or a pharmaceutically acceptable salt thereof, wherein:

L₁₉ and A are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₄₄ and R₄₅ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,cycloalkyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,—S(═O)₂R₂₀, —C(═O)R, or —N(R₁₃R₁₄); and

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀; and

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

In certain aspects of Structure (VIII), R₁ is hydrogen, cyano, C₁₋₆alkyl, C₁₋₆ alkoxy, or —C(═O)NN(R₁₃)(R₁₄).

In certain aspects of Structure (VIII), R₁ is cyano.

In certain aspects of Structure (VIII), R₂ is hydrogen or halo.

In certain aspects of Structure (VIII), R₂ is hydrogen.

In certain aspects of Structure (VIII), R₃ is hydrogen.

In certain aspects of Structure (VIII), R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (VIII), R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In certain aspects of Structure (VIII), R₃₉ is hydrogen.

In certain aspects of Structure (VIII), L₁₉ is N.

In certain aspects of Structure (VIII), A is N.

In certain aspects of Structure (VIII), A is CH.

In certain aspects, the compounds of Structure (VIII) have the followingStructure (VIII-D):

or a pharmaceutically acceptable salt thereof.

In various aspects, compounds of formula IX are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl) or —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R₂₄ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1;

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

L¹ is CR²³ or N;

L² is CH or N;

at least one of L¹ or L² is N; and

R²³ is H or C₁-C₄ straight or branched alkyl.

In some aspects of Structure (IX), R²⁴ is C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein tis 0 or 1.

In some aspects of Structure (IX), R²¹ is halogen, C₁-C₄ straight orbranched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom, —S(O)_(u)—(C₁-C₄ straight orbranched alkyl) wherein u is 0 or 2, or —S(O)_(u)—(C₃-C₅ cycloalkyl)wherein u is 0 or 2;

In some aspects of Structure (IX), R³ is H or halogen.

In some aspects of Structure (IX), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (IX), both L¹ and L² are N.

In some aspects of Structure (IX), R²¹ is C₁-C₂ alkyl or C₃-C₅cycloalkyl and R²² is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (IX), R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂alkyl) wherein t is 0 or 1.

In some aspects of Structure (IX), R²¹ is C₃-C₅ cycloalkyl, R₂₂ is C₁-C₂alkyl and R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl, R²² is C₁-C₂ alkyland R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl.

In some aspects of Structure (IX), R³ is H or F.

In some aspects of Structure (IX), R¹ is —CN.

In some aspects of Structure (IX), R¹ is —CF₃.

In some aspects of Structure (IX), R²² is H, methyl or ethyl.

In some aspects of Structure (IX), R²² is H.

In some aspects of Structure (IX), R²² is methyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is hydrogen, R³ isH or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴is methyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethoxy or ethoxy.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is CH, L² is N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L² is CH, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), compounds have a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (X) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH or halogen;

L³ is C(R⁶⁰)₂, O or NR⁵⁰;

each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or branchedalkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyl optionallycontaining an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂, C₁-C₄straight or branched alkyl wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom

R²² is H, halogen, C₁-C₂ alkyl;

each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:

t is 0 or 1, and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

s is 0, 1 or 2;

each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and

wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form aring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, twoR⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹.

In some aspects of Structure (X), R²¹ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl.

In some aspects of Structure (X), R³ H or halogen.

In some aspects of Structure (X), R¹ is —CN or C₁-C₂ haloalkyl.

In some aspects of Structure (X), R³ is H or F.

In some aspects of Structure (X), R¹ is —CN.

In some aspects of Structure (X), R¹ is —CF₃.

In some aspects of Structure (X), n is 1.

In some aspects of Structure (X), n is 2.

In some aspects of Structure (X), m is 1

In some aspects of Structure (X), m is 2.

In some aspects of Structure (X), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some aspects of Structure (X), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (X), n is 2, m is 1, L³ is —NC(O)—O—(C₁-C₂alkyl).

In some aspects of Structure (X), L³ is NR⁵⁰, R⁵⁰ is C₁-C₂ alkyl; R²¹ iscyclobutyl; R²² is H or methyl; R³ is H; R¹ is —CN; m is 2 and n is 1 or2.

In some aspects of Structure (X), n is 2, m is 1, L³ is O and s is 0.

In some aspects of Structure (X), R²² is H, methyl or ethyl.

In some aspects of Structure (X), R²² is methyl.

In some aspects of Structure (X), R²² is H.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R₃ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is NR⁵⁰ where R⁵⁰is methyl or ethyl.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is O.

In some aspects of Structure (X), the compound has a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (XI) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently H, halogen or C₁-C₄ straight or branched alkyl;

R³ is H, —OH, or halogen;

R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R²² is H, halogen, C₁-C₂ alkyl; and

R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In some aspects of Structure (XI), R³ is H or halogen.

In some aspects of Structure (XI), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (XI), R²¹ is C₃-C₄ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl.

In some aspects of Structure (XI), R³ is H or F.

In some aspects of Structure (XI), R¹ is —CN.

In some aspects of Structure (XI), R¹ is —CF₃.

In some aspects of Structure (XI), R²² is H, methyl or ethyl.

In some aspects of Structure (XI), R²² is H.

In some aspects of Structure (XI), R²² is methyl.

In some aspects of Structure (XI), R¹ is —CN, each R² is H, is H or F,R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl or ethyl.

In some aspects of Structure (XI), the compound has a structure selectedfrom the group consisting of:

In certain aspects, the present disclosure provides compounds having anyone of the structures found in Table 1. According to the presentdisclosure, the compounds of Table 1 are inhibitors of fatty acidsynthase.

Synthesis of Compounds

Also described herein are methods of synthesizing the compounds of thepresent disclosure. Compounds of the present disclosure can besynthesized as indicated in SYNTHETIC SCHEMES 1-13 below.

wherein:

R″ is hydrogen or alkyl;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄),

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino; and

R₁₇ is hydrogen or alkyl.

wherein:

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;

R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is absent if L₁is N, or R₂₃ and R₂₄ taken together with the atoms to which they areattached join together to form a heterocyclyl, heteroaryl, orcycloalkyl; and

R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄ taken together withthe atoms to which they are attached join together to form aheterocyclyl, heteroaryl, or cycloalkyl.

wherein:

LG is a leaving group;

Nu is a nucleophile;

L₂, L₃, L₄, and L_(4′) are each independently CH or N;

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino; and

R₁₇ is hydrogen or alkyl.

wherein:

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆ alkyl,alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;

R₁₇ is hydrogen or alkyl; and

R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆alkoxy)(heterocyclyl), or heterocyclyl.

wherein:

R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄),—(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;

q is 0, 1, 2, 3, or 4;

R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);

R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;

R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, alkyl, alkoxy,CF₃, —OCF₃, or —S(═O)₂R₂₀;

R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or—S(═O)₂R₂₀;

R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;

R₁₇ is hydrogen or alkyl;

R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆alkoxy)(heterocyclyl), or heterocyclyl;

R₂₉ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyalkyl, heteroaryl,heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆, or R₄₈C(═O)R₄₇;

R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,hydroxyalkyl aryl, heterocyclyl, heteroaryl, alkylamino, CF₃, —OCF₃,—S(═O)₂R₂₀, or —N(R₁₅R₁₆); and

m 0, 1, or 2.

Schemes 6-13 provides a synthesis for exemplary compounds of formula IXwherein:

R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ straight or branched alkyl) wherein:

C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen heteroatom;and

when R¹ is not H, —CN or halogen, it is optionally substituted with oneor more halogens;

each R² is independently hydrogen, halogen or C₁-C₄ straight or branchedalkyl;

R³ is H, —OH, or halogen;

R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅ cycloalkylwherein the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom;

R²² is H, halogen, or C₁-C₂ alkyl;

R²³ is H or C₁-C₄ straight or branched alkyl; and

R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)_(t)-OH,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:

t is 0 or 1; and

the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom.

Additional methods for producing particular compounds according to thepresent disclosure are provided in the EXAMPLES. One skilled in the artwill recognize that other compounds of structures can be made bymodifications to the specifically disclosed schemes employing methodsknown to those of skill in the art. Additional examples can be found inTable 1.

Many such techniques are well known in the aft However, many of theknown techniques are elaborated in Compendium of Organic SyntheticMethods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3, 1977; Vol. 4, 1980; Vol. 5,1984; and Vol. 6 as well as March in Advanced Organic Chemistry (1985);Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes (1993); Advanced OrganicChemistry Part B: Reactions and Synthesis, Second Edition (1983);Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, SecondEdition (1977); Protecting Groups in Organic Synthesis, Second Edition;and Comprehensive Organic Transformations (1999).

Viral Infection Pathways

The host cell targets inhibited by the present compounds and methodsplay a role in the viral replication and/or infection pathways.Targeting of such host cell targets modulates the replication and/orinfection pathways of the viruses. In preferred aspects the identifiedhost cell targets are directly or indirectly modulated using thecompositions of the present disclosure. The modulation of such host celltargets can also be performed by targeting entities in the upstream ordownstream signaling pathways of the host cell targets.

According to the present disclosure, viral infection can be treated bytargeting the fatty acid synthesis pathway, and in particular fatty acidsynthase. HRV is representative of viruses that can be treated accordingto the present disclosure. Like other viruses, the replication of HRVinvolves six phases; transmission, entry, replication, biosynthesis,assembly, and exit. Entry occurs by endocytosis, replication and vRNPassembly takes place in the nucleus, and the virus buds from the plasmamembrane. In the infected patient, the virus targets airway epithelialcells. The present compounds and methods target and modulate at leastone host cell targets involved in such pathways.

For some viruses a great deal of progress has been made in theelucidation of the steps involved during infection of host cells. Forexample, experiments initiated in the early 1980s showed that influenzavirus follows a stepwise, endocytic entry program with elements sharedwith other viruses such as alpha-and rhabdoviruses (Marsh and Helenius1989; Whittaker 2006). The steps include: 1) Initial attachment tosialic acid containing glycoconjugates receptors on the cell surface; 2)signaling induced by the virus particle; 3) endocytosis byclathrin-dependent and clathrin-independent cellular mechanism; 4)acid-induced, hemaglutinin (HA)-mediated penetration from lateendosomes; 5) acid-activated, M2 and matrix protein (M1) dependentuncoating of the capsid; and, 6) intra-cytosolic transport and nuclearimport of vRNPs. These steps depend on assistance from the host cell inthe form of sorting receptors, vesicle formation machinery,kinase-mediated regulation, organelle acidification, and, most likely,activities of the cytoskeleton,

Influenza attachment to the cells surface occurs via binding of the HA1subunit to cell surface glycoproteins and glycolipids that carryoligosaccharide moieties with terminal sialic acid residues (Skehel andWiley 2000). The linkage by which the sialic acid is connected to thenext saccharide contributes to species specificity. Avian strainsincluding H5N1 prefer an a-(2,3)-link and human strains a-(2,6)-link(Matrosovich 2006). In epithelial cells, binding occurs preferentiallyto microvilli on the apical surface, and endocytosis occurs at base ofthese extensions (Marlin 1982). Whether receptor binding induces signalsthat prepare the cell for the invasion is not yet known, but it islikely because activation of protein kinase C and synthesis ofphopshatidylinositol-3-phosphate (PI3P) are required for efficient entry(Sieczkarski et al. 2003; Whittaker 2006).

Endocytic internalization occurs within a few minutes after binding(Matlin 1982; Yoshimura and Ohnishi 1984). In tissue culture cellsinfluenza virus makes use of three different types of cellularprocesses; 1) preexisting clathrin coated pits, 2) virus-inducedclathrin coated pits, and 3) endocytosis in vesicles without visiblecoat (Matlin 1982; Sieczkarski and Whittaker 2002; Rust et al. 2004).Video microscopy using fluorescent viruses showed the virus particlesundergoing actin-mediated rapid motion in the cell periphery followed byminus end-directed, microtubule-mediated transport to the perinucleararea of the cell. Live cell imaging indicated that the virus particlesfirst entered a subpopulation of mobile, peripheral early endosomes thatcarry them deeper into the cytoplasm before penetration takes place(Lakadamyali et al. 2003; Rust et al. 2004). The endocytic process isregulated by protein and lipid kinases, the proteasome, as well as byRabs and ubiquitin-dependent sorting factors (Khor et al. 2003;Whittaker 2006).

The membrane penetration step is mediated by low pH-mediated activationof the trimeric, metastable HA, and the conversion of this Type I viralfusion protein to a membrane fusion competent conformation (Maeda et al,1981; White et al. 1982). This occurs about 16 min afterinternalization, and the pH threshold varies between strains in the5.0-5.6 range. The target membrane is the limiting membrane ofintermediate or late endosomes. The mechanism of fusion has beenextensively studied (Kielian and Rey 2006). Further it was observed thatfusion itself does not seem to require any host cell components except alipid bilayer membrane and a functional acidification system (Maeda etal. 1981; White et al. 1982). The penetration step is inhibited byagents such as lysosomotropic weak bases, carboxylic ionophores, andproton pump inhibitors (Matlin 1982; Whittaker 2006).

To allow nuclear import of the incoming vRNPs, the capsid has to bedisassembled. This step involves acidification of the viral interiorthrough the amantadine-sensitive M2-channels which causes dissociationof M1 from the vRNPs (Bukrinskaya et al. 1982; Martin and Helenius 1991;Pinto et al. 1992). Transport of the individual vRNPs to the nuclearpore complexes and transfer into the nucleus depends on cellular nucleartransport receptors (O'Neill et al. 1995; Cros et al. 2005). Replicationof the viral RNAs (synthesis of positive and negative strands), andtranscription occurs in complexes tightly associated with the chromatinin the nucleus. It is evident that, although many of the steps arecatalyzed by the viral polymerase, cellular factors are involvedincluding RNA polymerase activating factors, a chaperone HSP90, hCLE,and a human splicing factor UAP56. Viral gene expression is subject tocomplex cellular control at the transcriptional level, a control systemdependent on cellular kinases (Whittaker 2006).

The final assembly of an influenza particle occurs during a buddingprocess at the plasma membrane. In epithelial cells, budding occurs atthe apical membrane domain only (Rodriguez-Boulan 1983). First, theprogeny vRNPs are transported within the nucleoplasm to the nuclearenvelope, then from the nucleus to the cytoplasm, and finally theyaccumulate in the cell periphery. Exit from the nucleus is dependent onviral protein NEP and M1, and a variety of cellular proteins includingCRM1 (a nuclear export receptor), caspases, and possibly some nuclearprotein chaperones. Phosphorylation plays a role in nuclear export byregulating M1 and NEP synthesis, and also through the MAPK/ERK system(Bui et al. 1996; Ludwig 2006). G protein and protein kinase signalingis involved in influenza virus budding from infected host cells (Hui E.and Nayak D, 2002).

The three membrane proteins of the virus are synthesized, folded andassembled into oligomers in the ER (Dots et al. 1993). They pass throughthe Golgi complex; undergo maturation through modification of theircarbohydrate moieties and proteolytic cleavage. After reaching theplasma membrane they associate with M1 and the vRNPs in a buddingprocess that results in the inclusion of all eight vRNPs and exclusionof most host cell components except lipids.

Influenza infection is associated with activation of several signalingcascades including the MAPK pathway (ERK, JNK, p38 and BMK-1/ERK5), theIkB/NF-kB signaling module, the Raf/MEK/ERK cascade, and programmed celldeath (Ludwig 2006). These result in a variety of effects that limit theprogress of infection such as transcriptional activation of IFNb,apoptotic cell death, and a block in virus escape of from late endosomes(Ludwig 2006).

Most previous studies on virus-cell interactions were performed intissue culture using tissue culture- or egg-adapted virus strains. Theviruses in these examples were adapted in such a manner that changeswere induced that affected receptor binding and tropism (Matrosovich2006). Infection with wild-type pathogenic strains is provides a morenatural picture of viral interaction with host proteins. It is knownthat in the human airways influenza A and B primarily infect nonciliated epithelial cells in the upper respiratory track carrying NeuSAca-(2,6)-Gal, whereas avian strains infect ciliated epithelial cell witha-(2,3)-linked sialic acids deeper in the airways (Matrosovich et al.2004a).

Additionally, progress has been made in the elucidation of the stepsinvolved during infection by HRV of host cells. Selected events inrhinovirus infection of the normal human airway can be regarded asoccurring sequentially. Initial steps in rhinovirus pathogenesis arebelieved to include viral entry through the nose, mucociliary transportof virus to the posterior pharynx, and initiation of infection inciliated and non-ciliated epithelial cells of the upper airway. Viralreplication peaks on average within 48 h of initiation of infection andpersists for up to 3 wk. Infection is followed by activation of severalinflammatory mechanisms, which can include release or generation ofinterleukins, bradykinins, prostaglandins, and possibly histamine andstimulation of parasympathetic reflexes. Pathophysiologic processes areinitiated, which include vasodilatation of nasal blood vessels,transudation of plasma, glandular secretion, and stimulation of nervefibers, causing pain and triggering sneeze and cough reflexes. Theresultant clinical illness is a rhinosinusitis, pharyngitis, andbronchitis, which, on average, lasts one week.

Changes in gene expression profiles during in vivo rhinovirus infectionshave been identified (Proud D. et al. Am J Respir Crit Care Med Vol 178.pp 962-968, 2008). Nasal epithelial scrapings were obtained before andduring experimental rhinovirus infection, and gene expression wasevaluated by microarray. Viperin is identified as an antiviral proteininduced by interferon (IFN), viral infections, and pathogen-associatedmolecules. Naturally acquired rhinovirus infections, cultured humanepithelial cells, and short interfering RNA knockdown were used tofurther evaluate the role of viperin in rhinovirus infections. Symptomscores and viral titers were measured in subjects inoculated withrhinovirus or a sham control, and changes in gene expression wereassessed 8 and 48 hours after inoculation. Rhinovirus-induced changes ingene expression were not observed 8 hours after viral infection, but11,887 gene transcripts were significantly altered in scrapings obtained2 days post-inoculation. Major groups of up-regulated genes includechemokines, signaling molecules, interferon-responsive genes, andantivirals. Rhinovirus infection significantly alters the expression ofmany genes associated with the immune response, including chemokines andantivirals. Some of the genes markedly induced by HRV-16 infectioninclude but are not limited to CCL2, CCL8, CXCL11, CXCL10, CXCL13,CXCL9, CCL20, IFIT2, GBP1, IFIT1, GIP2, IFIT4, IL28B, IRF7, CIG5, NOS2A,OAS3, OASL, OAS2, OAS1, MX2, MX1, PLSCR_(1,) SOCS1, SOCS2, MDA5, RIGI,SOCS3, ICAM-1, HAPLN3, MMP12, EPSTI1, and TNC.

Fatty Acid Synthesis Pathway

Various aspects of the present disclosure relate to compositions andmethods that modulate the activity of the fatty acid synthesis pathwayto treat a viral infection or treat cancer. The fatty acid synthesispathway in humans can use four enzymes: 1) acetyl-CoA carboxylase (ACC),which can synthesize malonyl-CoA; 2) malic enzyme, which can produceNADPH; 3) citrate lyase, which can synthesize acetyl-CoA; and 4) fattyacid synthase, which can catalyze NADPH-dependent synthesis of fattyacids from acetyl-CoA and malonyl-CoA. In various aspects, the presentdisclosure relates to treatment of viral infections and cancer bymodulating the activity of the fatty acid synthase protein.

The final products of fatty acid synthase are free fatty acids which canuse separate enzymatic derivatization with coenzyme-A for incorporationinto other products. In humans, fatty acid synthesis can occur in twosites: the liver, where palmitic acid can be made (Roncari, (1974) Can.J. Biochem., 52:221-230) and lactating mammary gland, where C₁₀-C₁₄fatty acids can be made (Thompson, et al., (1985) Pediatr. Res.,19:139-143).

Fatty acids can be synthesized in the cytoplasm from acetyl-CoA.Acetyl-CoA can be generated from pyruvate by pyruvate dehydrogenase(PDH) and by β-oxidation of fatty acids in the mitochondria. A “citrateshuttle” can transport acetyl-CoA from the mitochondria to thecytoplasm. Acetyl-CoA can react with oxaloacetate to yield citrate, anda tricarboxylate translocase can transport citrate from the mitochondriato the cytosol. In the cytoplasm, citrate can be cleaved back tooxaloacetate and acetyl-CoA, a reaction that can be catalyzed byATP-citrate lyase. Oxaloacetate can be converted back to pyruvate forre-entry into mitochondria.

Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA carboxylase (ACC)is a complex multifunctional, biotin-containing, enzyme system that cancatalyze carboxylation of acetyl-CoA to malonyl-CoA. This conversion isan irreversible, rate-limiting step in fatty acid synthesis. ACC cancarry out three functions: biotin carboxyl carrier protein, biotincarboxylase and carboxyltransferase. ATP-dependent carboxylation ofbiotin, a prosthetic group (cofactor) can be followed by transfer of thecarboxyl group to acetyl-CoA.

HCO₃ ⁻ +ATP+acetyl-CoA→ADP+P_(i)+malonyl-CoA

There are two ACC forms, alpha and beta, encoded by two different genesACC-alpha (also known as ACC, ACAC, ACCI, ACCA, and ACACA) can encodeprotein highly enriched in lipogenic tissues. Multiple alternativelyspliced transcript variants divergent in the sequence and encodingdistinct isoforms have been found for this gene. ACC-beta (also known asACC2, ACCB, HACC275, and ACACB) can encode protein thought to controlfatty acid oxidation by means of the ability of malonyl-CoA to inhibitcarnitine-palmitoyl-CoA transferase I, the rate-limiting step in fattyacid uptake and oxidation by mitochondria. ACC-beta may be involved inthe regulation of fatty acid oxidation, rather than fatty acidbiosynthesis. There is evidence for the presence of two ACC-betaisoforms.

ACC can be regulated by the phosphorylation/dephosphorylation oftargeted serine residues. For example, AMP-activated kinase (AMPK) canphosphorylate ACC, and this phosphorylation can inhibit the ability ofACC to produce malonyl-CoA. On ACACA, AMPK can phosphorylate Ser79,Ser1200, and Ser1215 (Park S. H. et al. (2002) J. Appl. Physiol.92:2475-82). AMPK can phosphorylate Ser218 on ACACB (Hardie D. G. (1992)Biochim. Biophys. Acta 1123:231-8). Also, cAMP-dependent protein kinase(Protein Kinase A, or PKA) can phosphorylate ACC.

ACC can be regulated by allosteric transformation by citrate orpalmitoyl-CoA. For example, citrate can be a positive effector (i.e.citrate can allosterically activate ACC). Citrate concentration can behigh when there is adequate acetyl-CoA entering the Krebs Cycle. Excessacetyl-CoA can then be converted via malonyl-CoA to fatty acids.Palmitoyl-CoA can be a negative effector. Palmitoyl-CoA, which is theproduct of Fatty Acid Synthase (FASN), can promote the inactiveconformation of ACC, which can reduce production of malonyl-CoA (afeedback inhibition process). AMP can regulate fatty acid synthesis byregulating the availability of malonyl-CoA. Insulin binding a receptorcan activate a phosphatase to dephosphorylate ACC, which can remove theinhibitory effect.

The fatty acid synthase gene (also known as FAS, OA-519, SDR₂₇X1;MGC14367; MGC15706; FASN) is involved in fatty acid synthesis. Theenzyme encoded by this gene is a multifunctional protein ofapproximately 272 kDa with multiple domains, each with distinct enzymeactivities that can play a role in fatty acid biosynthesis. FASN cancatalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, inthe presence of NADPH, into long-chain saturated fatty acids. In somecancer cell lines, FASN protein has been found to be fused with estrogenreceptor-alpha (ER-alpha), in which the N-terminus of FASN is fusedin-frame with the C-terminus of ER-alpha.

FASN protein can exist in the cytosol as a dimer of identical subunits.FASN consists of three catalytic domains in the N-terminal section(-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), and dehydrase(DH)). The N-terminal section is separated by a core region of about 600amino acids from four C-terminal domains (enoyl reductase (ER),-ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase(TE)). The crystal structure of a mammalian fatty acid synthase has beenreported (Maier T. et al. (2008) Science 321: 1315-1322). Each of thecatalytic domains of FASN can be targeted in the methods of treatingviral infection of the provided invention.

The enzymatic steps of fatty acid synthesis can involve decarboxylativecondensation, reduction, dehydration, and another reduction and canresult in a saturated acyl moiety. NADPH can be an electron donor inreductive reactions.

Antiviral Activity

In various aspects, the present disclosure provides methods for treatingviral infection in a subject, the method comprising administering to asubject in need of such treatment an effective amount of a compound ofStructures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1.

In various aspects, the disclosure provides methods for treating a viralinfection, the method comprising administering the compounds of thepresent disclosure to a subject in need thereof the agent.

The present disclosure contemplates the treatment of any viral infectionthat targets the fatty acid synthesis pathway in a host, and inparticular by modulating the activity of fatty acid synthase. Forexample, the present methods can be used to treat influenza infection,adenovirus infection, respiratory syncytial virus infection, poxvirusinfection, poliomyelitis infection, hepatitis C infection, yellow feverinfection, dengue fever infection, rhinovirus infection, and the like.

In various aspects, the present disclosure provides methods for treatinghepatitis C infection by administering to the subject one or morecompounds disclosed herein. In modulating the FASN pathway in thesubject, hepatitis C infection is treated. It has been shown thatexpression of FASN is upregulated in human hepatoma cell line Huh7 whenthese cells are infected with HCV. Inhibiting FASN production with aFASN inhibitor reduced the production of HCV. Thus administration to asubject of the compounds of the present disclosure. (Yang, W. et al.(2008) Hepatology 48(5):1396-1403). It is demonstrated in the EXAMPLESthat FASN inhibition correlates to inhibition of HCV.

In certain aspects, the methods of inhibiting viral infection can beperformed in vitro. In further aspects, the methods of inhibiting viralinfection can be performed in vivo.

In certain aspects the compounds of the present disclosure may be usedin combination with other antiviral treatments in the treating of viralinfection.

In various aspects, the viral infection is a human yellow feverinfection. In further aspects, the viral infection is a human hepatitisC infection. In yet further aspects, the viral infection is a humanrhinoviral infection.

In various aspects the compounds of the present disclosure can be usedfor the treatment of infection of an animal subject, such as a human, byany of a plethora of viruses.

In certain aspects, the compounds of the present disclosure can be usedfor the inhibition of a host by a respiratory virus. Respiratory virusesare most commonly transmitted by airborne droplets or nasal secretionsand can lead to a wide spectrum of illness. Respiratory viruses includethe respiratory syncytial virus (RSV), influenza viruses, coronavirusessuch as SARS, adenoviruses, parainfluenza viruses and rhinoviruses(HRV).

According to one aspect, the present disclosure can be used to treatinfection by HRV. The genus of rhinoviruses is a member of thePicornaviridae family of viruses. Genera within the family include theGenus Enterovirus, Rhinovirus, Cardiovirus, Aphthovirus, Hepatovirus,Parechovirus, Erbovirus, Kobuvirus, Teschovirus. Human rhinoviruses(HRV) include the most common viruses that infect humans and can causethe common cold. HRV are lytic in nature. Rhinoviruses havesingle-stranded positive sense RNA genomes of between 7.2 and 8.5 kb inlength. At the 5′ end of these genomes is a virus-encoded protein, andlike mammalian mRNA, there is also a 3′ poly-A tail. The 5′-terminal UMPof the viral RNA is covalently linked to the small viral protein VPg(Paul A V, et al. Nature 1998, 393(6682):280-284). The 5′UTR containstwo structural elements. One is the 5′-cloverleaf structure involved inthe plus-strand RNA synthesis and in the process of switching fromtranslation to replication (Huang H, et al. Biochemistry 2001,40(27):8055-8064). The other is the internal ribosomal entry site (IRES)which promotes translation of the polyprotein. In addition,species-specific internal cis-acting replication elements (cre) havebeen identified in human enteroviruses (HEV), HRV-A and HRV-B (Gerber K,Wimmer E, Paul A V, J Virol 2001, 75(22):10979-10990). The viralparticles themselves are not enveloped and are icosahedral in structure.Rhinoviruses also grow best in temperatures between 33-35° C. They arealso sensitive to acidic environment.

HRV viral proteins are transcribed as a single long polypeptide, whichis cleaved into the viral structural and nonstructural proteins.Rhinoviruses are composed of a capsid that contains four viral proteinsVP1, VP2, VP3 and VP4 (Rossmann M, et al. 1985 Nature 317 (6033):145-53; Smith T, et al. 1986, Science 233 (4770): 1286-93). Theisometric nucleocapsids are 22-40 nm in diameter. VP1, VP2, and VP3 formthe major part of the protein capsid. The much smaller VP4 protein has amore extended structure and lies at interface between the capsid and theRNA genome. There are 60 copies of each of these proteins assembled asan icosahedron. Human antibodies that target epitopes lying on theexterior regions of VP1-VP3 play a role in the immune response to HRVs.

HRVs have two general modes of transmission: 1) via aerosols ofrespiratory droplets and 2) from contaminated surfaces, including directperson-to-person contact. The primary route of entry for rhinoviruses isthe upper respiratory tract. Afterwards, an HRVbinds to ICAM-1(Inter-Cellular Adhesion Molecule 1) also known as CD54 (Cluster ofDifferentiation 54) receptors on respiratory epithelial cells. As thevirus replicates and spreads, infected cells release chemokines andcytokines, which in turn activate inflammatory mediators. Infectionoccurs rapidly, with the rhinovirus adhering to surface receptors within15 minutes of entering the respiratory tract. The incubation period isgenerally 8-10 hours before symptoms begin to occur. HRVs are the mostfrequent cause of infection across all age groups of the humanpopulation. Replication is often restricted to the upper respiratorytract leading to self-limited illnesses such as the common cold.However, HRV infections can also exacerbate pre-existing airwaydisorders, invade the lower respiratory tract and lead to seriouscomplications.

In another aspect, the compounds of the present disclosure can be usedfor the treatment of infection by the influenza virus by targeting thepathways that the virus relies on for infection or replication.Influenza viruses belong to Orthomyxoviridae family of viruses. Thisfamily also includes Thogoto viruses and Dhoriviruses. There are severaltypes and subtypes of influenza viruses known, which infect humans andother species. Influenza type A viruses infect people, birds, pigs,horses, seals and other animals, but wild birds are the natural hostsfor these viruses. Influenza type A viruses are divided into subtypesand named on the basis of two proteins on the surface of the virus:hemagglutinin (HA) and neuraminidase (NA). For example, an “H7N2 virus”designates an influenza A subtype that has an HA 7 protein and an NA 2protein. Similarly an “H5N1” virus has an HA 5 protein and an NA 1protein. There are 16 known HA subtypes and 9 known NA subtypes. Manydifferent combinations of HA and NA proteins are possible. Only someinfluenza A subtypes (i.e., H1N1, H1N2, and H3N2) are currently ingeneral circulation among people. Other subtypes are found most commonlyin other animal species. For example, H7N7 and H3N8 viruses causeillness in horses, and H3N8 also has recently been shown to causeillness in dogs (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Antiviral agents which target host cell proteins involved in influenzainfection can be used to protect high-risk groups (hospital units,institutes caring for elderly, immuno-suppressed individuals), and on acase by case basis. A potential use for antiviral agents is to limit thespread and severity of the future pandemics whether caused by avian H5N1or other strains of influenza virus. Avian influenza A viruses of thesubtypes H5 and H7, including H5N1, H7N7, and H7N3 viruses, have beenassociated with high pathogenicity, and human infection with theseviruses have ranged from mild (H7N3, H7N7) to severe and fatal disease(H7N7, H5N1). Human illness due to infection with low pathogenicityviruses has been documented, including very mild symptoms (e.g.,conjunctivitis) to influenza-like illness. Examples of low pathogenicityviruses that have infected humans include H7N7, H9N2, and H7N2 (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza B viruses are usually found in humans but can also infectseals. Unlike influenza A viruses, these viruses are not classifiedaccording to subtype. Influenza B viruses can cause morbidity andmortality among humans, but in general are associated with less severeepidemics than influenza A viruses. Although influenza type B virusescan cause human epidemics, they have not caused pandemics. (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza type C viruses cause mild illness in humans and do not causeepidemics or pandemics. These viruses can also infect dogs and pigs.These viruses are not classified according to subtype. (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza viruses differ from each other in respect to cell surfacereceptor specificity and cell tropism, however they use common entrypathways. The compounds of the present disclosure advantageously targetpathways that are common to multiple viruses giving rise to broaderantiviral activity. Thus, the present compounds can also prove usefulagainst unrelated viruses that use similar pathways. For example, theagents can protect airway epithelial cells against a number of differentviruses in addition to influenza viruses.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by adenoviruses. Most adenovirusescommonly cause respiratory illness; symptoms of respiratory illnesscaused by adenovirus infection range from the common cold syndrome topneumonia, croup, and bronchitis. Patients with compromised immunesystems are especially susceptible to severe complications of adenovirusinfection. Acute respiratory disease (ARD), first recognized amongmilitary recruits during World War II, can be caused by adenovirusinfections during conditions of crowding and stress. Adenoviruses aremedium-sized (90-100 nm), nonenveloped icosohedral viruses containingdouble-stranded DNA. There are 49 immunologically distinct types (6subgenera: A through F) that can cause human infections. Adenovirusesare unusually stable to chemical or physical agents and adverse pHconditions, allowing for prolonged survival outside of the body. Someadenoviruses, such as AD2 and Ad5 (species C) use clathrin mediatedendocytosis and macropinocytosis for infectious entry. Otheradenoviruses, such as Ad3 (species B) use dynamin dependent endocytosisand macropinocytosis for infectious entry.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by respiratory syncytial virus (RSV). RSVis the most common cause of bronchiolitis and pneumonia among infantsand children under 1 year of age. Illness begins most frequently withfever, runny nose, cough, and sometimes wheezing. During their first RSVinfection, between 25% and 40% of infants and young children have signsor symptoms of bronchiolitis or pneumonia, and 0.5% to 2% requirehospitalization. Most children recover from illness in 8 to 15 days. Themajority of children hospitalized for RSV infection are under 6 monthsof age. RSV also causes repeated infections throughout life, usuallyassociated with moderate-to-severe cold-like symptoms; however, severelower respiratory tract disease can occur at any age, especially amongthe elderly or among those with compromised cardiac, pulmonary, orimmune systems. RSV is a negative-sense, enveloped RNA virus. The virionis variable in shape and size (average diameter of between 120 and 300nm), is unstable in the environment (surviving only a few hours onenvironmental surfaces), and is readily inactivated with soap and waterand disinfectants.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by human parainfluenza virus (HPIV).HPIVs are second to respiratory syncytial virus (RSV) as a common causeof lower respiratory tract disease in young children. Similar to RSV,HPIV's can cause repeated infections throughout life, usually manifestedby an upper respiratory tract illness (e.g., a cold and/or sore throat).HPIVs can also cause serious lower respiratory tract disease with repeatinfection (e.g., pneumonia, bronchitis, and bronchiolitis), especiallyamong the elderly, and among patients with compromised immune systems.Each of the four HPIVs has different clinical and epidemiologicfeatures. The most distinctive clinical feature of HPIV-1 and HPIV-2 iscroup (i.e., laryngotracheobronchitis); HPIV-1 is the leading cause ofcroup in children, whereas HPIV-2 is less frequently detected. BothHPIV-1 and -2 can cause other upper and lower respiratory tractillnesses. HPIV-3 is more often associated with bronchiolitis andpneumonia. HPIV-4 is infrequently detected, possibly because it is lesslikely to cause severe disease. The incubation period for HPIVs isgenerally from 1 to 7 days. HPIVs are negative-sense, single-strandedRNA viruses that possess fusion and hemagglutinin-neuraminidaseglycoprotein “spikes” on their surface. There are four serotypes typesof HPIV (1 through 4) and two subtypes (4a and 4b). The virion varies insize (average diameter between 150 and 300 nm) and shape, is unstable inthe environment (surviving a few hours on environmental surfaces), andis readily inactivated with soap and water.

In various aspects, the compounds of the present disclosure can be usedfor the treatment of infection by coronavirus. Coronavirus is a genus ofanimal virus belonging to the family Coronaviridae. Coronaviruses areenveloped viruses with a positive-sense single-stranded RNA genome and ahelical symmetry. The genomic size of coronaviruses ranges fromapproximately 16 to 31 kilobases, extraordinarily large for an RNAvirus. The name “coronavirus” is derived from the Latin corona, meaningcrown, as the virus envelope appears under electron microscopy to becrowned by a characteristic ring of small bulbous structures. Thismorphology is actually formed by the viral spike peplomers, which areproteins that populate the surface of the virus and determine hosttropism. Coronaviruses are grouped in the order Nidovirales, named forthe Latin nidus, meaning nest, as all viruses in this order produce a 3′co-terminal nested set of subgenomic mRNA's during infection. Proteinsthat contribute to the overall structure of all coronaviruses are thespike, envelope, membrane and nucleocapsid. In the specific case of SARSa defined receptor-binding domain on S mediates the attachment of thevirus to its cellular receptor, angiotensin-converting enzyme 2.

The present disclosure contemplates the treatment of any viral infectionthat targets the fatty acid synthesis pathway in a host, and inparticular by modulating the activity of fatty acid synthase. Forexample, the present methods can be used to treat infections caused byAbelson leukemia virus, Abelson murine leukemia virus, Abelson's virus,Acute laryngotracheobronchitis virus, Adelaide River virus, Adenoassociated virus group, Adenovirus, African horse sickness virus,African swine fever virus, AIDS virus, Aleutian mink disease parvovirus,Alpharetrovirus, Alphavirus, ALV related virus, Amapari virus,Aphthovirus, Aquareovirus, Arbovirus, Arbovirus C, arbovirus group A,arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus,Argentine hemorrhagic fever virus, Arterivirus, Astrovirus, Atelineherpesvirus group, Aujezky's disease virus, Aura virus, Ausduk diseasevirus, Australian bat lyssavirus, Aviadenovirus, avian erythroblastosisvirus, avian infectious bronchitis virus, avian leukemia virus, avianleukosis virus, avian lymphomatosis virus, avian myeloblastosis virus,avian paramyxovirus, avian pneumoencephalitis virus, avianreticuloendotheliosis virus, avian sarcoma virus, avian type Cretrovirus group, Avihepadnavirus, Avipoxvirus, B virus, B19 virus,Babanki virus, baboon herpesvirus, baculovirus, Barmah Forest virus,Bebaru virus, Berrimah virus, Betaretrovirus, Birnavirus, Bittner virus,BK virus, Black Creek Canal virus, bluetongue virus, Bolivianhemorrhagic fever virus, Boma disease virus, border disease of sheepvirus, borna virus, bovine alphaherpesvirus 1, bovine alphaherpesvirus2, bovine coronavirus, bovine ephemeral fever virus, bovineimmunodeficiency virus, bovine leukemia virus, bovine leukosis virus,bovine mammillitis virus, bovine papillomavirus, bovine papularstomatitis virus, bovine parvovirus, bovine syncytial virus, bovine typeC oncovirus, bovine viral diarrhea virus, Buggy Creek virus, bulletshaped virus group, Bunyamwera virus supergroup, Bunyavirus, Burkitt'slymphoma virus, Bwamba Fever, CA virus, Calicivirus, Californiaencephalitis virus, camelpox virus, canarypox virus, canid herpesvirus,canine coronavirus, canine distemper virus, canine herpesvirus, canineminute virus, canine parvovirus, Cano Delgadito virus, caprine arthritisvirus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus,Cardiovirus, caviid herpesvirus 1, Cercopithecid herpesvirus 1,cercopithecine herpesvirus 1, Cercopithecine herpesvirus 2, Chandipuravirus, Changuinola virus, channel catfish virus, Charleville virus,chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, chubreovirus, chum salmon virus, Cocal virus, Coho salmon reovirus, coitalexanthema virus, Colorado tick fever virus, Coltivirus, Columbia SKvirus, common cold virus, contagious ecthyma virus, contagious pustulardermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpoxvirus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus cricketparalysis virus, Crimean-Congo hemorrhagic fever virus, croup associatedvirus, Cryptovirus, Cypovirus, Cytomegalovirus, cytomegalovirus group,cytoplasmic polyhedrosis virus, deer papillomavirus, deltaretrovirus,dengue virus, Densovirus, Dependovirus, Dhori virus, diploma virus,Drosophila C virus, duck hepatitis B virus, duck hepatitis virus 1, duckhepatitis virus 2, duovirus, Duvenhage virus, Deformed wing virus DWV,eastern equine encephalitis virus, eastern equine encephalomyelitisvirus, EB virus, Ebola virus, Ebola-like virus, echo virus, echovirus,echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus,EIA virus, EIA virus, encephalitis virus, encephalomyocarditis groupvirus, encephalomyocarditis virus, Enterovirus, enzyme elevating virus,enzyme elevating virus (LDH), epidemic hemorrhagic fever virus,epizootic hemorrhagic disease virus, Epstein-Barr virus, equidalphaherpesvirus 1, equid alphaherpesvirus 4, equid herpesvirus 2,equine abortion virus, equine arteritis virus, equine encephalosisvirus, equine infectious anemia virus, equine morbillivirus, equinerhinopneumonitis virus, equine rhinovirus, Eubenangu virus, European elkpapillomavirus, European swine fever virus, Everglades virus, Eyachvirus, fetid herpesvirus 1, feline calicivirus, feline fibrosarcomavirus, feline herpesvirus, feline immunodeficiency virus, felineinfectious peritonitis virus, feline leukemia/sarcoma virus, felineleukemia virus, feline panleukopenia virus, feline parvovirus, felinesarcoma virus, feline syncytial virus, Filovirus, Flanders virus,Flavivirus, foot and mouth disease virus, Fort Morgan virus, FourCorners hantavirus, fowl adenovirus 1, fowlpox virus, Friend virus,Gammaretrovirus, GB hepatitis virus, GB virus, German measles virus,Getah virus, gibbon ape leukemia virus, glandular fever virus, goatpoxvirus, golden shinner virus, Gonometa virus, goose parvovirus,granulosis virus, Gross' virus, ground squirrel hepatitis B virus, groupA arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pigtype C virus, Hantaan virus, Hantavirus, hard clam reovirus, harefibroma virus, HCMV (human cytomegalovirus), hemadsorption virus 2,hemagglutinating virus of Japan, hemorrhagic fever virus, hendra virus,Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus group,hepatitis C virus, hepatitis D virus, hepatitis delta virus, hepatitis Evirus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus,hepatitis virus, hepatitis virus (nonhuman), hepatoencephalomyelitisreovirus 3, Hepatovirus, heron hepatitis B virus, herpes B virus, herpessimplex virus, herpes simplex virus herpes simplex virus 2, herpesvirus,herpesvirus 7, Herpesvirus ateles, Herpesvirus hominis, Herpesvirusinfection, Herpesvirus saimiri, Herpesvirus suis, Herpesvirusvaricellae, Highlands J virus, Hirame rhabdovirus, hog cholera virus,human adenovirus 2, human alphaherpesvirus 1, human alphaherpesvirus 2,human alphaherpesvirus 3, human B lymphotropic virus, humanbetaherpesvirus 5, human coronavirus, human cytomegalovirus group, humanfoamy virus, human gammaherpesvirus 4, human gammaherpesvirus 6, humanhepatitis A virus, human herpesvirus 1 group, human herpesvirus 2 group,human herpesvirus 3 group, human herpesvirus 4 group, human herpesvirus6, human herpesvirus 8, human immunodeficiency virus, humanimmunodeficiency virus 1, human immunodeficiency virus 2, humanpapillomavirus, human T cell leukemia virus, human T cell leukemia virusI, human T cell leukemia virus II, human I cell leukemia virus III,human T cell lymphoma virus I, human T cell lymphoma virus II, human Tcell lymphotropic virus type 1, human T cell lymphotropic virus type 2,human T lymphotropic virus I, human T lymphotropic virus II, human Tlymphotropic virus III, Ichnovirus, infantile gastroenteritis virus,infectious bovine rhinotracheitis virus, infectious haematopoieticnecrosis virus, infectious pancreatic necrosis virus, influenza virus A,influenza virus B, influenza virus C, influenza virus D, influenza viruspr8, insect iridescent virus, insect virus, iridovirus, Japanese B virus, Japanese encephalitis virus, JC virus, Junin virus, Kaposi'ssarcoma-associated herpesvirus, Kemerovo virus, Kilharn's rat virus,Klamath virus, Kolongo virus, Korean hemorrhagic fever virus, kumbavirus, Kysanur forest disease virus, Kyzylagach virus, La Crosse virus,lactic dehydrogenase elevating virus, lactic dehydrogenase virus, Lagosbat virus, Langur virus, lapine parvovirus, Lassa fever virus, Lassavirus, latent rat virus, LCM virus, Leaky virus, Lentivirus,Leporipoxvirus, leukemia virus, leukovirus, lumpy skin disease virus,lymphadenopathy associated virus, Lymphocryptovirus, lymphocyticchoriomeningitis virus, lymphoproliferative virus group, Machupo virus,mad itch virus, mammalian type B oncovirus group, mammalian type Bretroviruses, mammalian type C retrovirus group, mammalian type Dretroviruses, mammary tumor virus, Mapuera virus, Marburg virus,Marburg-like virus, Mason Pfizer monkey virus, Mastadenovirus, Mayarovirus, ME virus, measles virus, Menangle virus, Mengo virus, Mengovirus,Middelburg virus, milkers nodule virus, mink enteritis virus, minutevirus of mice, MLV related virus, MM virus, Mokola virus.Molluscipoxvirus, Molluscum contagiosum virus, monkey B virus, monkeypoxvirus, Mononegavirales, Morbillivirus, Mount Elgon bat virus, mousecytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus,mouse K virus, mouse leukemia virus, mouse mammary tumor virus, mouseminute virus, mouse pneumonia virus, mouse poliomyelitis virus, mousepolyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus,Mucambo virus, mucosal disease virus, mumps virus, murid betaherpesvirus1, murid cytomegalovirus 2, murine cytomegalovirus group, murineencephalomyelitis virus, murine hepatitis virus, murine leukemia virus,murine nodule inducing virus, murine polyomavirus, murine sarcoma virus,Muromegalovirus, Murray Valley encephalitis virus, myxoma virus,Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheepdisease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus,Neethling virus, Nelson Bay virus, neurotropic virus, New WorldArenavirus, newborn pneumonitis virus, Newcastle disease virus, Nipahvirus, noncytopathogenic virus, Norwalk virus, nuclear polyhedrosisvirus (NPV), nipple neck virus, O'nyong'nyong virus, Ockelbo virus,oncogenic virus, oncogenic viruslike particle, oncornavirus, Orbivirus,Orf virus, Oropouche virus, Orthohepadnavirus, Orthomyxovirus,Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovinecatarrhal fever virus, owl monkey herpesvirus, Palyam virus,Papillomavirus, Papillomavirus sylvilagi, Papovavirus, parainfluenzavirus, parainfluenza virus type 1, parainfluenza virus type 2,parainfluenza virus type 3, parainfluenza virus type 4, Paramyxovirus,Parapoxvirus, paravaccinia virus, Parvovirus, Parvovirus B19, parvovirusgroup, Pestivirus, Phlebovirus, phocine distemper virus, Picodnavirus,Picornavirus, pig cytomegalovirus—pigeonpox virus, Piry virus, Pixunavirus, pneumonia virus of mice, Pneumovirus, poliomyelitis virus,poliovirus, Polydnavirus, polyhedral virus, polyoma virus, Polyomavirus,Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2,Polyomavirus maccacae 1, Polyomavirus muris 1, Polyomavirus muris 2,Polyomavirus papionis 1, Polyomavirus papionis 2, Polyomavirussylvilagi, Pongine herpesvirus 1, porcine epidemic diarrhea virus,porcine hemagglutinating encephalomyelitis virus, porcine parvovirus,porcine transmissible gastroenteritis virus, porcine type C virus, poxvirus, poxvirus, poxvirus variolae, Prospect Hill virus, Provirus,pseudocowpox virus, pseudorabies virus, psittacinepox virus, quailpoxvirus, rabbit fibroma virus, rabbit kidney vaculolating virus, rabbitpapillomavirus, rabies virus, raccoon parvovirus, raccoonpox virus,Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus,Rauscher's virus, recombinant vaccinia virus, recombinant virus,reovirus, reovirus 1, reovirus 2, reovirus 3, reptilian type C virus,respiratory infection virus, respiratory syncytial virus, respiratoryvirus, reticuloendotheliosis virus, Rhabdovirus, Rhabdovirus carpia,Rhadinovirus, Rhinovirus, Rhizidiovirus, Rift Valley fever virus,Riley's virus, rinderpest virus, RNA tumor virus, Ross River virus,Rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeolavirus, Rubivirus. Russian autumn encephalitis virus, SA 11 simian virus,SA2 virus, Sabia virus, Sagiyama virus, Saimirine herpesvirus 1,salivary gland virus, sandfly fever virus group, Sandjimba virus, SARSvirus, SDAV (sialodacryoadenitis virus), sealpox virus, Semliki ForestVirus, Seoul virus, sheeppox virus, Shope fibroma virus, Shope papillomavirus, simian foamy virus, simian hepatitis A virus, simian humanimmunodeficiency virus, simian immunodeficiency virus, simianparainfluenza virus, simian T cell lymphotrophic virus, simian virus,simian virus 40, Simplexvirus, Sin Nombre virus, Sindbis virus, smallpoxvirus, South American hemorrhagic fever viruses, sparrowpox virus,Spumavirus, squirrel fibroma virus, squirrel monkey retrovirus, SSV 1virus group, STLV (simian T lymphotropic virus) type I, STLV (simian Tlymphotropic virus) type II, STLV (simian T lymphotropic virus) typeIII, stomatitis papulosa virus, submaxillary virus, suidalphaherpesvirus 1, suid herpesvirus 2, Suipoxvirus, swamp fever virus,swinepox virus, Swiss mouse leukemia virus, TAC virus, Tacaribe complexvirus, Tacaribe virus, Tanapox virus, Taterapox virus, Tench reovirus,Theiler's encephalomyelitis virus, Theiler's virus, Thogoto virus,Thottapalayam virus, Tick borne encephalitis virus, Tioman virus,Togavirus, Torovirus, tumor virus, Tupaia virus, turkey rhinotracheitisvirus, turkeypox virus, type C retroviruses, type D oncovirus, type Dretrovirus group, ulcerative disease rhabdovirus, Una virus, Uukuniemivirus group, vaccinia virus, vacuolating virus, varicella zoster virus,Varicellovirus, Varicola virus, variola major virus, variola virus,Vasin Gishu disease virus, VEE virus, Venezuelan equine encephalitisvirus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagicfever virus, vesicular stomatitis virus, Vesiculovirus, Vilyuisk virus,viper retrovirus, viral haemorrhagic septicemia virus, Visna Maedivirus, Visna virus, volepox virus, VSV (vesicular stomatitis virus),Wallal virus, Warrego virus, wart virus. WEE virus, West Nile virus,western equine encephalitis virus, western equine encephalomyelitisvirus, Whataroa virus, Winter Vomiting Virus, woodchuck hepatitis Bvirus, woolly monkey sarcoma virus, wound tumor virus, WRSV virus, Yabamonkey tumor virus, Yaba virus, Yatapoxvirus, yellow fever virus, andthe Yug Bogdanovac virus.

Utility in Metabolic Disorders

In various aspects, the compounds of the present disclosure have utilityin the treating of metabolic diseases. FASN has been demonstrated to beinvolved in regulation of glucose, lipids and cholesterol metabolism.Mice with a liver-specific inactivation of FASN have normal physiologyunless fed a zero-fat diet, in which case they develop hypoglycemia andfatty liver, both of which are reversed with dietary fat. (Chakravarthy,M. V., et al. (2005) Cell Metabolism 1:309-322). Db/+ mice fed a highfructose diet exhibit reduced liver triglyceride levels and improvedinsulin sensitivity when treated for 28 days with platensimycin, acovalent inhibitor of FASN. (Wu, M. et al. (2011) PNAS108(13):5378-5383). Ambient glucose levels are also reduced in db/dbmice following treatment with platensimycin. These results provideevidence that inhibiting FASN can yield therapeutically relevantbenefits in animal models of diabetes and related metabolic disorders.Thus the disclosed FASN inhibitors are useful in the treatment ofdisorders characterized by disregulation in these systems. Withoutlimitation, examples include steatosis and diabetes.

Non-alcoholic liver disease (NAFLD), a condition in which the livercontains more than 5% fat by weight which is not caused by alcoholconsumption, is a disease which currently affects ˜20-30% of the US andgeneral western world population, and is associated with a significantincreased risk of morbidity extending beyond the liver to cardiovasculardisease, chronic kidney disease and malignancy. Obesity and themetabolic syndrome are two key risk factors for NAFLD which arecharacterized as an imbalance in energy utilization and storage. Thisimbalance leads to dysregulated metabolic pathways and inflammatoryresponses that drive further changes leading to liver damage andcomorbid conditions. Along with the progression of metabolic syndrome,NAFLD leads to more advanced liver disease starting with non-alcoholicsteatohepatitis (NASH) which can then progress to significant liverdiseases including cirrhosis and hepatocellular carcinoma.

The synthesis of fatty acids in the liver, a pathway termed hepatic denovo lipogenesis (DNL), is increased in subjects with metabolic syndromeand NAFLD. The DNL pathway not only produces fatty acids that contributeto elevated liver stores of triglycerides, but the fatty acids that areproduced are saturated fatty acid species, primarily palmitate (C16:0),which contribute to signaling events that increase liver inflammation.Free palmitate fatty acid has also been implicated in liver inflammationprocesses such as macrophage recruitment and activation of endoplasmicreticulum stress response.

In various embodiments, the compounds of the present disclosure (e.g.,Compound 364A) can act prophylactically to prevent progression ofsymptoms of NASH such as elevated levels of AST and ALT, livertriglycerides and cholesterol, liver steatosis, liver inflammation,liver ballooning, liver fibrosis, and NAFLD activity score. Forinstance, Example 7 demonstrates that compounds of the disclosure (e.g.,Compound 364A) can inhibit the progression of metabolic diseases such asliver disease (e.g., NASH).

In addition, the compounds of the present disclosure (e.g., Compound364A) can reverse the symptoms of NASH in models of establishedNASH-type disease. For instance, Example 10 demonstrates that Compoundsof the present disclosure can reduce levels of AST, ALT livertriglycerides and cholesterol as well as symptoms such as liversteatosis, liver inflammation, liver ballooning, liver fibrosis, andNAFLD activity score in mice that had established NASH after 44 weeks ofhigh-fat, fructose, cholesterol diet. In Example 10, the NASH diseaseprogression was advanced to the point of showing fibrosis before themice were dosed with drug. The data showed a dose response in all majorindicators of disease progression.

Accordingly, in various aspects, the present disclosure provides methodsfor treating NASH or symptoms of NASH in a subject, the methodcomprising administering to a subject in need of such treatment aneffective amount of a compound of Structures (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1. Infurther aspects, compounds having Structure (I), (II), (III), (IV), (V),(VI), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used forthe manufacture of a medicament for treating NASH or symptoms of NASH.In further aspects, compounds having Structure (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 canbe used for treating NASH or symptoms of NASH. In some embodiments, theNASH is established in the subject, and treatment with a compound of thepresent disclosure can reduce or eliminate the symptoms and etiology ofNASH, e.g. general steatosis, steatosis of the liver, steatohepatitis,inflammation, inflammation of the liver, lysosomal acid lipasedeficiency, and liver cirrhosis, etc. In other embodiments, thetreatment is used prophylactically to prevent the on-set ofnon-alcoholic fatty liver disease (NAFLD), the on-set of NASH, theprogression of NAFLD to NASH or halt progression of NASH disease.Whether treating prophylactically or established NAFLD or NASH disease,the treatment of fatty liver disease reduces the risk factors associatedwith establishment or progressing diabetes, liver cancer, cardiovasculardisease, high triglycerides, kidney disease and metabolic syndrome.

Accordingly, in some embodiments, the present disclosure provides amethod of treating non-alcoholic steatohepatitis comprisingadministering to the subject in need thereof a compound having Structure(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or asprovided in Table 1 wherein the method comprises reversing at least onesymtpom of established non-alcoholic steatohepatitis. In someembodiments, the method comprises preventing the progression of at leastone symptom of non-alcoholic steatohepatitis. In some embodiments, thesymptom is selected from elevated levels of AST; elevated levels of ALT;elevated levels of liver triglycerides; elevated levels of cholesterol;liver steatosis; liver inflammation; liver ballooning; liver fibrosis;and NAFLD activity score.

Furthermore, as set forth in Example 12, compounds of the presentdisclosure (e.g., Compound 364A) were found to reduce fibrotic geneexpression in human liver cells. Accordingly, in some embodiments,compounds of the disclosure can reduce fibrotic gene expression (e.g.,Col 1a1, αSMA, PPDGFR, TGFbR_(1,) TIMP1, TIMP2, and/or MMP2). In someembodiments, the gene expression can return after withdrawal of thecompounds (e.g., Compound 364A). Accordingly, without wishing to bebound by theory, the downregulation of the fibrotic genes is not a toxiceffect of a compound of the present disclosure.

Accordingly, in various aspects, the present disclosure provides methodsfor reducing fibrotic gene expression in a subject (e.g., in thesubject's liver cells), the method comprising administering to a subjectin need of such treatment an effective amount of a compound ofStructures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1. In further aspects, compounds havingStructure (I), (II), (III), (IV), (V), (VI), (VIII), (IX), (X), (XI) oras provided in Table 1 can be used for the manufacture of a medicamentfor reducing fibrotic gene expression (e.g., in liver cells). In furtheraspects, compounds having Structure (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can be used forreducing fibrotic gene expression (e.g., in liver cells).

Cardiovascular disease is closely linked to the progression of metabolicsyndrome. However, NAFLD is also a strong predictor of cardiovasculardisease, such as increased risk of carotid atherosclerotic plaques andendothelial dysfunction, which is independent of the existence ofmetabolic syndrome (Francis W. B., et. als., “De novo lipogenesis in theliver in health and disease: more than just a shunting yard forglucose.” Biol. Rev. (2016), 91, pp. 452-468). NAFLD has also beenimplicated as an independent factor contributing to the development oftype II diabetes. The rate of incidence of pre-diabetes or type IIdiabetes is 2.6 times higher in individuals with NAFLD, suggesting anindependent role in the pathogenesis of type II diabetes beyond initialinsulin resistance (Francis W. B., Biol. Rev. (2016), pp. 452-468; Bae,J. C., et. als., “Combined effect of nonalcoholic fatty liver diseaseand impaired fasting glucose on the development of type 2 diabetes.”Diabetes Care, 2011, 34, 727-729). Therefore DNL is an important pathwayfor therapeutic intervention to reduce the consequences associated withmetabolic syndrome and NAFLD (Bae, J. C., Diabetes Care, 2011, 727-729).

NAFLD and NASH have been associated with obesity and diabetes in humanswith high fat and high caloric diets. The synthesis of fatty acids inthe liver (i.e., synthesized via the hepatic de novo lipogenesis (DNL)pathway), is increased in subjects with metabolic syndrome and NAFLD.One of the key enzymes in DNL is fatty acid synthase (FASN). While thereare promising associations between FASN, DNL and NAFLD, there is verylittle evidence that direct inhibition of FASN is a competent mechanismfor treating NAFLD or controlling the progression of hepatic steatosis.Some literature reports of direct intervention at FASN by gene knock outor small molecule inhibitors give results which suggest an exacerbationof liver steatosis; the exact opposite effect needed to treat NAFLD orNASH. These results teach that FASN inhibition would not be expected toreduce hepatic steatosis or be a suitable mechanism to control theunderlying metabolic dysregulation or inflammation signaling which drivethe progression of fatty liver disease.

For example, liver-specific FASN knockout mice have been shown to havenormal livers when maintained on a standard diet. Unexpectedly, when ona zero-fat/high carbohydrate diet, the mice develop fatty livers(hepatic steatosis) and hypoglycemia showing that complete inhibition ofFASN in the liver of a mammal on a fat-restricted diet results in thedevelopment of NAFLD, the precursor of NASH (Chakravarthy, M. V., etal., “New hepatic fat activates PPARalpha to maintain glucose, lipid,and cholesterol homeostasis,” Cell Metabol. 1(5), 2005, 309-322). Whenthe knockout mice are fed a normal diet, no effect on metabolism ordevelopment of hepatic steatosis resulting from complete inhibition ofFASN by knockout is observed indicating that FASN inhibition in theliver would either have no effect on a mammal consuming a fat-containingdiet or would induce a fatty liver state (leading to NAFLD and NASH) ina mammal consuming a low fat/high carbohydrate diet, providing theopposite effect needed for treating NASH.

Small molecule inhibitors of FASN have been used to assess insulinresistance and hepatic steatosis. In a recent study in obese insulinresistant Zucker rats (Type II diabetes model), inhibition of de novolipogenesis with a small molecule FASN inhibitor did not improve insulinsensitivity and actually increased the level of fat in the liver (i.e.,hepatic steatosis). FASN inhibitors have also been shown to inhibithepatic de novo lipogenesis, but resulted in increased hepatic steatosisor fat deposits in the liver (“A Novel Fatty Acid Synthase Inhibitor(FASi) Suppresses De Novo Lipogenesis but induces Hepatic Steatosis,Dermatitis and does not enhance Insulin Sensitivity in Obese ZuckerRats,” Am. Diabetes Assoc. 68th Scientific Sessions, Jun. 6-10, 2008,San Francisco, Calif., poster 58LB; WO2008059214). These studies showthat direct inhibition of FASN reduces fat synthesis in the liver, butresults in acceleration in the development of NAFLD and. NASH in anobese diabetic mammal. Thus, FASN inhibition would not be expected tohave a therapeutic effect on fatty liver disease in obese and diabeticindividuals who have the highest risk of developing NAFLD and NASHdisease.

The FASN inhibitors of the present application were tested for activityagainst NAFLD. Unexpectedly, the FASN inhibitors of the presentapplication have demonstrated efficacy in a rodent model of NAFLD andlowering of pro-inflammatory IL-1beta (IL-1β) in rats on a high fatdiet. The FASN inhibitors of the present application have alsodemonstrated anti-inflammatory activity in cells, specifically reductionof IL-1β in human peripheral blood mononuclear cells (PBMC) andmonocytes cells, and have been shown to modulate the differentiation ofmouse and human CD4+ naïve T cells which resulted in a reduction of Th₁₇(pro-inflammatory T helper cells) and stimulation of T_(reg)(anti-inflammatory regulatory T) cells.

The FASN inhibitors of the present application are useful forcontrolling NAFLD in rodents, reducing pro-inflammatory cytokines, suchas IL-1β, and modulating T cell differentiation from pro-inflammatorycells, such as Th₁₇ cells, to anti-inflammatory T_(reg) cells. The FASNinhibitors of the present application can be used to treat variousaspects of metabolic syndrome including non-alcoholic liver disease(NAFLD) and the more advanced disease, non-alcoholic steatohepatitis(NASH). If left untreated, these liver dysfunction disease states canprogress to significant liver diseases, including liver cirrhosis, astate in which the liver shows steatosis, inflammation, fibrosis,steatohepatitis, and may progress to liver cancer (hepatocellularcarcinoma). Liver cirrhosis can have direct health consequences due tothe liver dysfunction including spider angiomata or spider nevi, palmarerythema, gynecomastia, hypogonadism, ascites, fetor hepaticus,jaundice, portal hypertension which causes splenomegaly, esophagealvarices, caput medusa, Hepatic encephalopathy, and acute kidney injury(particularly hepatorenal syndrome). In some embodiments, the compoundsof the present disclosure can be used to treat metabolic syndrome,non-alcoholic liver disease (NAFLD), non-alcoholic steatohepatitis(NASH), liver cirrhosis, liver fibrosis, and/or liver cancer(hepatocellular carcinoma).

The FASN inhibitor compounds of the present application can also be usedto treat inflammatory diseases by inducing changes in inflammationinducing cytokines. Example of inflammatory diseases that can be treatedwith FASN inhibitor compounds of the present application, include, butare not limited to, inflammatory diseases involving IL-1beta, such asdiseases responsive to IL-1beta blockade or associated with increasedIL-1beta expression; Familial Mediterranean fever (FMF); Pyogenicarthritis, pyoderma gangrenosum, acne (PAPA); Cryopyrin-associatedperiodic syndromes (CAPS); Hyper IgD syndrome (HMS); Adult and juvenileStill disease; Schnitzler syndrome; TNF receptor-associated periodicsyndrome (TRAPS); Blau syndrome; Sweet syndrome; Deficiency in IL-1receptor antagonist (DIRA); Recurrent idiopathic pericarditis;Macrophage activation syndrome (MAS); Urticarial vasculitis;Antisynthetase syndrome; Relapsing chondritis; Behçet disease;Erdheim-Chester syndrome (histiocytosis); Synovitis, acne, pustulosis,hyperostosis, osteitis (SAPHO); Rheumatoid arthritis; Periodic fever,aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA); Uratecrystal arthritis (gout); Type 2 diabetes; Smoldering multiple myeloma;Postmyocardial infarction heart failure; Osteoarthritis;Transfusion-related acute lung injury; Ventilator-induced lung injury;Pulmonary fibrosis including Idiopathic; Chronic obstructive pulmonarydisease (COPD); and Asthma.

The FASN inhibitors of the present application can also be used to treatdisease or conditions associated with elevated levels of inflammatory Tcells and/or reduced or inadequate levels of anti-inflammatory T cells,or to treat diseases or conditions in which the modulation ofdifferentiation of white blood cells (i.e., T cells) away from T helpercells and increasing anti-inflammatory T regulatory (T_(reg)) cellswould be beneficial. T_(reg) cells are essential for immune toleranceand play a crucial role in the limitation of excessive immune andinflammatory responses executed by T helper cells (i.e., Th₁, Th₂, Th₉,Th₁₇, etc.). Thus, shunting the differentiation of T helper cells toregulatory T cells by FASN inhibition can be used to treat inflammatorydiseases.

Treatment with a FASN inhibitor of the present application can inhibitthe maturation of T cells to T helper inflammatory cells (T-helper cellsthat can be inhibited include, but are not limited to, Th₁, Th₂, Th₉,and Th₁₇) and promotes their differentiation into T_(reg) cells. NaiveCD4+ cells differentiate into T helper and regulatory T cells to executetheir immunologic function. The differentiation depends on the presenceof cytokines. While T helper cells such as Th₁₇ cells play an importantrole in the protective immune response against intracellular pathogens,excessive immune responses exerted by these T helper cells also causeautoimmune and inflammatory diseases. Examples of immune-mediateddiseases that can be treated by the FASN inhibitors of the presentapplication include, but are not limited to, psoriasis, rheumatoidarthritis, multiple sclerosis, ankylosing spondylitis, inflammatorybowel disease (IBD), Chronic obstructive pulmonary disease (COPD),asthma, tumorigenesis, and transplant rejection. (Laura, A., et. al.,“Th17 cells in human disease,” Immunol. Rev. 223, 2008, 87-113; Lee, Y.,et. al. “Unexpected targets and triggers of autoimmunity. J. Clin.Immunol., 34 Suppl 1, 2014, S56-60)

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of disorders characterized by disregulation in these systemsincluding, but not limited to, nonalcoholic fatty acid disease (NAFLD),non-alcoholic steatohepatitis (NASH), steatosis and diabetes. In oneembodiment, the present disclosure relates to a method of treatingnon-alcoholic steatohepatitis (NASH) with FASN inhibitor compounds ofthe disclosure (i.e., a compound of Formula (I), (II), (III), (IV),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV),(XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

In another embodiment, the present disclosure relates to a method oftreating non-alcoholic steatohepatitis nonalcoholic fatty acid disease(NAFLD) with FASN inhibitor compounds of the disclosure (i.e., acompound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),(XVIII), (XIX) or (XX)).

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of metabolic syndrome. In one embodiment, the presentdisclosure relates to a method of treating metabolic syndrome with acompound of the disclosure i.e., a compound of Formula (I), (II), (III),(IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII),(XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of liver cirrhosis. In one embodiment, the present disclosurerelates to a method of treating liver cirrhosis with a compound of thedisclosure (i.e., a compound of Formula (I), (II), (III), (IV), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), (XVIII), (XIX) or (XX)).

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of liver fibrosis. In one embodiment, the present disclosurerelates to a method of treating liver fibrosis with a compound of thedisclosure (i.e., a compound of Formula (I), (II), (III), (IV), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), (XVIII), (XIX) or (XX)).

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of inflammation. In one embodiment, the present disclosurerelates to a method of treating inflammation with a compound of thedisclosure (i.e., a compound of Formula (I), (II), (III), (IV), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), (XVIII), (XIX) or (XX)).

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of a disease or condition in which interleukin 1 beta (IL1β)levels are elevated. In one embodiment, the present disclosure relatesto a method of treating a disease or condition in which interleukin 1beta (IL1β) levels are elevated with a compound of the disclosure (i.e.,a compound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),(XVIII), (XIX) or (XX)). In some embodiments, the disease or conditionin which interleukin 1 beta (IL1β) levels are elevated is selected fromFamilial Mediterranean fever (FMF), Pyogenic arthritis, pyodermagangrenosum, acne (PAPA), Cryopyrin-associated periodic syndromes(CAPS), Hyper IgD syndrome (HIDS), Adult and juvenile Still disease,Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS),Blau syndrome; Sweet syndrome, Deficiency in IL-1 receptor antagonist(DIRA), Recurrent idiopathic pericarditis, Macrophage activationsyndrome (MAS), Urticarial vasculitis, Anti synthetase syndrome,Relapsing chondritis, Behçet disease, Erdheim-Chester syndrome(histiocytosis), Synovitis, acne, pustulosis, hyperostosis, osteitis(SAPHO), Rheumatoid arthritis, Periodic fever, aphthous stomatitis,pharyngitis, adenitis syndrome (PFAPA), Urate crystal arthritis (gout),Type 2 diabetes, Smoldering multiple myeloma, Postmyocardial infarctionheart failure, Osteoarthritis, Transfusion-related acute lung injury,Ventilator-induced lung injury, Pulmonary fibrosis including Idiopathic,Chronic obstructive pulmonary disease and Asthma.

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of a disease or condition in which t-helper (T_(h)) celllevels are elevated. In one embodiment, the present disclosure relatesto a method of treating a disease or condition in which t-helper (T_(h))cell levels are elevated with a compound of the disclosure (i.e., acompound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),(XVIII), (XIX) or (XX)). In some embodiments, the disease or conditionin which t-helper (T_(h)) cell levels are elevated is selected fromPsoriasis, Rheumatoid arthritis, Multiple sclerosis, Ankylosingspondylitis, inflammatory bowel disease, asthma, tumorigenesis andtransplant rejection.

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of a disease or condition in which regulatory t cells(T_(reg)) are reduced or suppressed. In one embodiment, the presentdisclosure relates to a method of treating a disease or condition inwhich regulatory t cells (T_(reg)) are reduced or suppressed with acompound of the disclosure (i.e., a compound of Formula (I), (II),(III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII),(XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)). In someembodiments, the disease or condition in which regulatory t cells(T_(reg)) are reduced or suppressed is selected from Psoriasis,Rheumatoid arthritis, Multiple sclerosis, Ankylosing spondylitis,inflammatory bowel disease, asthma, tumorigenesis and transplantrejection.

In some embodiments, the disclosed FASN inhibitors a compound of Formula(I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),(XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)) mayalso be used in combination with one or more other therapeutic agents inthe treatment of a disease or condition related to fatty liver ormetabolic syndrome, including, but not limited to, steatosis, glucosemetabolism and lipogenesis. Such therapeutic agents include, but are notlimited to, (1) Stearoyl-coenzyme A desaturase 1 enzyme (SCDI)inhibitors, e.g., Aramchol; (2) Fibroblast growth factors (FGFs)agonists, e.g., BMS-986036; (3) Peroxisome proliferator activated α/δreceptor agonists, e.g., Elafibranor, aleglitazar, muraglitazar andtesaglitazar; (4) Glucagon-like peptide-1 (GLP-1) agonists, e.g.,Liraglutide, exenatide, lixisenatide, albiglutide, dulaglutide,taspoglutide, and semaglutide; (5) Liver X receptor alpha (LXR-α)inhibitors, e.g. Oltipraz; (6) Dipeptidyl peptidase (DPP4) inhibitors,e.g., Sitagliptin; (7) Peroxisome proliferator-activated receptor(PPAR)-γ agonists, e.g., thiazolidinediones, Rosiglitazone,Pioglitazone, Lobeglitazone, Ciglitazone, Darglitazone, Englitazone,Netoglitazone, and Rivoglitazone; (8) Biguanides, e.g., Metformin,buformin, and phenformin; (9) Statins or anti-absorbents, e.g.,Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin,Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe,SCH-48461, Niacin, Taurine, and Orlistat; (10) Antihyperlipidemic agentsand fibrates e.g., Gemfibrozil, Bezafibrate, Ciprofibrate, Clofibrate,Fenofibrate, Clinofibrate, pentoxifylline, and ursodiol; (11) Alphaglucosidase inhibitors, e.g., Acarbose; (12) PPARα ligands, e.g., N-3polyunsaturated fatty acids, Eicosapentaenoic acid (EPA), anddocosahexaenoic acid (DHA); (13) FXR agonists, e.g., Obeticholic acid(INT-747), and Px-104; (14) Sodium-dependent bile acid transportersinhibitors, e.g., SHP626; (15) SGLT2 inhibitors e.g., Remogliflozin,canagliflozin, dapagliflozin, and empagliflozin; and (15) Acetyl-CoACarboxylase (ACC) Inhibitors, e.g., ND-630, ND-654, NDI-010976(GS-0976), CP-640186, and PF-05175157.

In some embodiments, the disclosed FASN inhibitors (i.e., a compound ofFormula (I), (II), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX))may also be used in combination with one or more other therapeuticagents in the treatment of a disease or condition related to fatty liveror metabolic syndrome. Such therapeutic agents include, but are notlimited to, (1) immune signaling modulators; (2) TLR antagonists or TLR4antagonists, e.g., JKB-121, 2; (13) Inhibitors of the synthesis ofTNF-α, e.g., Pentoxifylline; (4) Angiotensin II type 1 blockers, e.g.,telmisartan, losartan, Valsartan, Telmisartan, Irbesartan, Azilsartan,and Olmesartan; and (5) Mediators of pro-inflammatory signaling, e.g.,IMM-124E, FGF19, and NGM282.

In some embodiments, the disclosed FASN inhibitors (i.e., a compound ofFormula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX),(X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or(XX)) may also be used in combination with one or more other therapeuticagents used to reduce oxidative stress for the treatment of a disease orcondition related to fatty liver or metabolic syndrome. Such therapeuticagents include, but are not limited to, (1) Apoptosis signal-regulatingkinase (ASK1) inhibitors which work to mitigate the profibrotic responseto ROS and (2) other mediators of oxidative stress, e.g., GS-4997 andVitamin E.

In some embodiments, the disclosed FASN inhibitors (i.e., a compound ofFormula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX),(X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX) or (XX))may also be used in combination with one or more anti-fibrosis treatmentagents in the treatment condition related to fatty liver or metabolicsyndrome. Such anti-fibrosis treatment agents include, but are notlimited to, (1) Inhibitors of C—C chemokine receptors or dual inhibitorof C—C chemokine receptor type 2 (CCR2) and C—C chemokine receptor type5 (CCR5) pathways, e.g., Cenicriviroc; (2) Galectin antagonists orgalectin-3 antagonist, e.g., GR-MD-02; (3) Angiotensin receptor blockers(ARB) which disrupt the reninangiotensin system, e.g., Losartan; (4)Lysyloxidase-Like 2 (LOXL2) inhibitors, e.g., Simtuzumab; and (5)Mediators of fibrosis, e.g., Vitamin A, Vitamin C, and Vitamin D.

In some embodiments, the disclosed FASN inhibitors (i.e., a compound ofFormula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII), (IX),(X), (XI), (XII), (XIII), (XIV), (XV), (XVII), (XVII), (XVIII), (XIX) or(XX)) may also be used in combination with one or more other apoptosisinhibitor agents in the treatment of a disease or condition related tofatty liver or metabolic syndrome. Such apoptosis inhibitor agentsinclude, but are not limited to, (1) Caspase inhibitors, e.g., GS-9450or Emricasan; and (2) Galectin protein inhibitors, e.g., GR-4TD-02 orGCS-100.

Anticancer Activity

In various aspects, the present disclosure provides methods for treatingcancer in subject, the method comprising administering to a subject inneed of such treatment an effective amount of a compound of Structures(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or asprovided in Table 1. In further aspects, compounds having Structure (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or asprovided in Table 1 can be used for the manufacture of a medicament fortreating cancer.

In certain aspects, the present disclosure provides a method forinhibiting tumor cell growth in a subject, the method comprisingadministering to a subject in need of such treatment an effective amountof a compound of Structure (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI) or as provided in Table 1. In further aspects,the tumor can be derived from ovary, breast, lung, thyroid, lymph node,kidney, ureter, bladder, ovary, teste, prostate, bone, skeletal muscle,bone marrow, stomach, esophagus, small bowel, colon, rectum, pancreas,liver, smooth muscle, brain, spinal cord, nerves, ear, eye, nasopharynx,oropharynx, salivary gland, or heart tissue. In certain aspects, thepresent compounds can be administered concurrently with one or moreadditional anti-cancer treatments.

In various aspects, the disclosed FASN inhibitors are useful in thetreatment of liver cancer. In one embodiment, the present disclosurerelated to a method of treating liver cancer with a compound of thedisclosure (i.e., a compound of Formula (I), (II), (III), (IV), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), (XVIII), (XIX) or (XX)).

Rapidly proliferating cancer cells activate the fatty acid synthesispathway to supply the high levels of lipids needed for membrane assemblyand oxidative metabolism. (Flavin, R. et al. (2010) Future Oncology.6(4):551-562) Inhibitors of fatty acid synthesis have demonstrated invivo activity in preclinical cancer models. (Orita, H. et al. (2007)Clinical Cancer Research. 13(23):7139-7145 and Puig, T. et al. (2011)Breast Cancer Research, 13(6):R₁₃₁) Additionally, fatty acid synthesissupports new blood vessel formation and inhibitors of this pathway haveactivity in in vitro models of angiogenesis. (Browne, C. D., et al.(2006) The FASEB Journal, 20(12):2027-2035). The presently disclosedcompounds demonstrated the ability to selectively induce cell-cyclearrest in HUVEC cells without causing general cell death by apoptosis.See EXAMPLES.

The cancer treatment of the present invention includes an anti-tumoreffect that may be assessed by conventional means such as the responserate, the time to disease progression and/or the survival rate.Anti-tumor effects of the present invention include, but are not limitedto, inhibition of tumor growth, tumor growth delay, regression of tumor,shrinkage of tumor, increased time to regrowth of tumor on cessation oftreatment and slowing of disease progression. For example, it isexpected that when the combination of the present invention isadministered to a warm-blooded animal such as a human, in need oftreatment for cancer involving a solid tumor, such a method of treatmentwill produce an effect, as measured by, for example, one or more of: theextent of the anti-tumor effect, the response rate, the time to diseaseprogression and the survival rate.

Skin Fibrosis

In various aspects, the present disclosure provides methods for treatingskin fibrosis in subject, the method comprising administering to asubject in need of such treatment an effective amount of a compound ofStructures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1. In further aspects, compounds havingStructure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1 can be used for the manufacture of amedicament for treating skin fibrosis. In further aspects, compoundshaving Structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),(X), (XI) or as provided in Table 1 can be used for treating skinfibrosis.

For instance, as set forth in Example 11, compounds of the presentdisclosure (e.g., Compound 364A) can reduce skin collagen content in ableomycin-induced murine skin fibrosis model. As set forth in Example11, FASN inhibition using compounds of the disclosure was able to reduceskin collagen content whether treatment was concurrent with bleomycininjection, or whether treatment was begun after bleomycin injection(e.g., 1 week after injection, 2 weeks after injection). Accordingly,compounds of the disclosure can be used to prevent the progression ofsymptoms of skin fibrosis such as collagen buildup. Compounds of thedisclosure can also be used to reverse the symptoms of skin fibrosis.

Methods of Treatment

Also provided herein are pharmaceutical compositions comprising thecompounds of the present disclosure. The present compositions andmethods have antiviral and/or anticancer activity.

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Structures (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) and apharmaceutically acceptable carrier, excipient, or diluent.

In certain aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Table 1 and apharmaceutically acceptable carrier, excipient, or diluent.

Certain aspects of the present disclosure relates to methods of usingpharmaceutical compositions and kits comprising one or more agents thatinhibit the fatty acid synthesis pathway to inhibit or decrease a viralinfection or for the treatment of cancer. Certain aspects of the presentdisclosure relates to methods of using pharmaceutical compositions andkits comprising one or more agents that inhibit fatty acid synthase toinhibit or decrease a viral infection or for the treatment of cancer.Another aspect of the present invention provides methods, pharmaceuticalcompositions, and kits for the treatment of animal subjects having aviral infection or cancer or at risk of developing a viral infection orcancer. The term “subject” as used herein includes humans as well asother mammals. The term “treating” as used herein includes achieving atherapeutic benefit and/or a prophylactic benefit By therapeutic benefitis meant eradication or amelioration of the underlying viral infection.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying viral infection such that an improvement is observedin the animal subject, notwithstanding the fact that the subject canstill be afflicted with the underlying virus.

In other aspects, the present invention relates to a method of treatingfatty liver disease in a subject in need thereof, the method comprisingadministering to the subject a fatty acid synthase inhibitor havingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In other aspects, the present invention relates to a method of treatingnon-alcoholic steatohepatitis nonalcoholic fatty acid disease (NAFLD) ina subject in need thereof, the method comprising administering to thesubject a fatty acid synthase inhibitor having Formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV),(XV), (XVI), (XVII), (XVIII), (XIX), or (XX).

In other aspects, the present invention relates to a method of treatingnon-alcoholic steatohepatitis (NASH) in a subject in need thereof, themethod comprising administering to the subject a fatty acid synthaseinhibitor having Formula (I), (II), (IV), (V), (VI), (VII), (VIII),(IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII),(XIX), or (XX).

In other aspects, the present invention relates to a method of treatingliver cirrhosis in a subject in need thereof, the method comprisingadministering to the subject a fatty acid synthase inhibitor havingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In other aspects, the present invention relates to a method of treatingliver fibrosis in a subject in need thereof, the method comprisingadministering to the subject a fatty acid synthase inhibitor havingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In other aspects, the present invention relates to a method of treatinginflammation in a subject in need thereof, the method comprisingadministering to the subject a fatty acid synthase inhibitor havingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In other aspects, the present invention relates to a method of treatingof a disease or condition in which interleukin 1 beta (IL1β) levels areelevated in a subject in need thereof, the method comprisingadministering to the subject a fatty acid synthase inhibitor havingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In other aspects, the present invention relates to a method of treatingof a disease or condition in which t-helper (T_(h)) cell levels areelevated in a subject in need thereof, the method comprisingadministering to the subject a fatty acid synthase inhibitor havingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In other aspects, the present invention relates to a method of treatingof a disease or condition in which regulatory t cells (T_(reg)) arereduced or suppressed in a subject in need thereof, the methodcomprising administering to the subject a fatty acid synthase inhibitorhaving Formula (I), (II), (III), (IV), (V), (VI), (VII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In other aspects, the present invention relates to a method of treatingliver cancer in a subject in need thereof, the method comprisingadministering to the subject a fatty acid synthase inhibitor havingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or(XX).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) wherein R₃ is F.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compounds of Formula (I) wherein A is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) wherein A is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) wherein X, Y, and Z are NR′.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) wherein R₄ is heteroaryl,heterocyclyl, —C(═O)N(R₅R₆), —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆alkoxy, or R₄ and R₁₁.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-E).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-F).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-G).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-H).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-I).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-J).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-K).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-L).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-M).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-N).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-O).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-P).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-Q).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-R).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-S).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-T).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-U).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-V).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-W).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-X).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-Y).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-Z).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AA).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AB).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AC).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AD).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AE).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AF).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AG).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (I) having a Formula (I-AH).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (II) having a Formula (II-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (II) having a Formula (II-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (II) having a Formula (II-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (II) having a Formula (II-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (II) having a Formula (II-E).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (II) having a Formula (II-F).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (III) having a Formula (III-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (III) having a Formula (III-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (III) having a Formula (III-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (III) having a Formula (III-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (III) having a Formula (III-E).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (III) having a Formula (III-F).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₁ is hydrogen, cyano,C₁₋₆ alkyl, C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₁ is cyano.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₂ is hydrogen or halo;R₂ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₃ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₂₅ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein L₂ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein L₁ is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein L₃ is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein L₄ is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein A is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein A is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₂₆ is heterocyclyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein R₂₄ is —N(R₁₃)(R₁₄).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein L₅ and L₆ are eachindependently N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein s is 1.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) wherein s is 0.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-E).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-F).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-G).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-H).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-I).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-J).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-K).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-L).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-M).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-N).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IV) having a Formula (IV-O).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein L₇ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein L₇ is O.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein A is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein A is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₁ is hydrogen, cyano,C₁₋₆ allyl, C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₁ is cyano.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₂ is hydrogen or halo.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₂ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₃ is fluorine.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₃₁ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₃₀ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein L₈ is O.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein L₉ is O.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein L₁₀ is O and L₁₁ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein L₁₂ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) wherein R₃₂ and R₃₃ are eachindependently hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-I).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-K).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-L).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-M).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-N).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (V) having a Formula (V-O).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₁ is hydrogen, cyano,C₁₋₆ alkyl, C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₁ is cyano.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₂ is hydrogen or halo.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₂ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₃ is fluorine.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₃₅ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₃₄ is heteroaryl;

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein R₃₄ is thienyl, pyrryl,furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl,imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl,pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,thiadiazolyl, benzothiazolyl, or benzothiadiazolyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein L₁₃ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein L₁₄ and L₁₅ are eachindependently CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein A is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) wherein A is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-E).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-F).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-G).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-H).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VI) having a Formula (VI-I).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₁ is hydrogen, cyano,C₁₋₆ alkyl, C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₁ is cyano.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₂ is hydrogen or halo.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₂ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₃ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₁₉ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₄₀ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein L₁₆ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein L₁₇ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein L₁₈ is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein L₁₈ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein A is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein A is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₄₂ is C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) wherein R₄₁ is C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) having a Formula (VII-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) having a Formula (VII-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) having a Formula (VII-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VII) having a Formula (VII-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₁ is hydrogen, cyano,C₁₋₆ alkyl, C₁₋₆ alkoxy, or —C(═O)NN(R₁₃)(R₁₄).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₁ is cyano.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₂ is hydrogen orhalo.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₂ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₃ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein R₃₉ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein L₁₉ is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein A is N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) wherein A is CH.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) having a Formula (VIII-A).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) having a Formula (VIII-B).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) having a Formula (VIII-C).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VIII) having a Formula (VIII-D).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²⁴ is C₁-C₄ straight orbranched alkyl or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branchedalkyl), wherein t is 0 or 1.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²¹ is halogen, C₁-C₄straight or branched alkyl or C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R³ is H or halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein both L¹ and L² are N.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²¹ is C₁-C₂ alkyl orC₃-C₅ cycloalkyl and R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²¹ is C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²⁴ is —(C₁-C₂alkyl)_(t)-O—(C₁-C₂ alkyl) wherein t is 0 or 1.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²¹ is C₃-C₅ cycloalkyl,R²² is C₁-C₂ alkyl and R²⁴ is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²¹ is cyclobutyl, R²²is C₁-C₂ alkyl and R²⁴ is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²¹ is cyclobutyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R³ is H or F.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R¹ is —CF₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²² is H, methyl orethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R²² is methyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R¹ is —CN, each R² is H,R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N,and R²⁴ is methoxy or ethoxy.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R¹ is —CN, each R² is H,R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is CH, L² is N,and R²⁴ is methyl, ethyl, hydroxymethyl, methoxymethyl, or2-methoxyethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein R¹ is —CN, each R² is H,R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L² is CH,and R²⁴ is methyl, ethyl, hydroxymethyl, methoxymethyl, or2-methoxyethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (IX) wherein the compound selectedfrom:

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R²¹ is halogen, C₁-C₄straight or branched alkyl or C₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R³ is H or halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R¹ is —CN or C₁-C₂haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R³ is H or F.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R¹ is —CF₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein n is 1.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein n is 2.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein m is 1.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein m is 2.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R²¹ is C₁-C₂ alkyl orC₃-C₅ cycloalkyl and R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R²¹ is C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein n is 2, m is L³ is

—N—C(O)—O—(C₁-C₂ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein L³ is NR⁵⁰; R⁵⁰ is C₁-C₂alkyl; R²¹ is cyclobutyl; R²² is H or methyl; R³ is H; R¹ is —CN; m is 2and n is 1 or 2.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein n is 2, m is L³ is O ands is 0.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R²² is H, methyl orethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R²² is methyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R¹ is —CN, each R² is H,R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ isNR⁵⁰ wherein R⁵⁰ is methyl or ethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein R¹ is —CN, each R² is H,R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ isO.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (X) wherein the compound selectedfrom:

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³ is H or halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R²¹ is cyclobutyl andR²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R²¹ is cyclobutyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³ is H or F.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R¹ is —CF₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R²² is H, methyl orethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R²² is methyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³⁵ is —C(O)—NH R³⁵¹.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³⁵¹ is isopropyl,isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³⁵¹ is(R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R¹ is —CN, each R² isH, R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—NHR³⁵¹where R³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or(S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³⁵ is —C(O)—O—R³⁵¹.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³⁵¹ is isopropyl,isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R³⁵¹ is(R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein R¹ is —CN, each R² isH, R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—O—R³⁵¹where R³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or(S)-tetrahydro-2H-pyran-3-yl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (VJ-I) wherein the compound selectedfrom:

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R³ is H or halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R¹ is halogen, —CN, orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R²¹ is C₃-C₄ cycloalkyland R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R²¹ is cyclobutyl andR²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R²¹ is cyclobutyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R³ is H or F.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R¹ is —CF₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R²² is H, methyl orethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R²² is methyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein R¹ is —CN, each R² is H,R³ is H or F, R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl orethyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XI) wherein the compound selectedfrom:

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein L-Ar is

Ar is not

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²¹ is halogen, C₁-C₄alkyl or C₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²¹ is C₁-C₄ alkyl orC₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²¹ is C₁-C₂ alkyl orC₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R₂₁ is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²¹ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²¹ is H or C₁-C₂alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²² is H or —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²² is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is H, —CN, —(C₁-C₄alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,—(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is H, C₁-C₄ alkyl,—(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is C₁-C₄ alkyl or—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is —(C₁-C₂alkyl)-O—(C₁-C₂ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is —CH₂—O—CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is C₃-C₆cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is —CN or —(C₁-C₂alkyl)-CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is —(C₁-C₂alkyl)-CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is H, —CH₃, —CH₂OH,—CH₂OCH₃, —(CH₂)₂OH, —(CH₂)₂OCH₃ or —(CH₂)₂N(CH₃)₂.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is methyl,isopropyl, cyclopropyl, —CN, or —(C₁-C₂ alkyl)-CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is substituted withone or more substituents selected from C₁-C₂ alkyl, oxo, —CN, halogen,alkanoyl, alkoxycarbonyl, —OH and C₁-C₂ alkoxy.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is substituted withone or more substituents selected from methyl, —F, methoxy, —C(═O)CH₃and —C(═O)—OCH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is substituted withtwo substituents that are the same or different.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁴ is substituted withthree substituents that are the same or different.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is halogen, —CN,C₁-C₂ alkyl or cyclopropyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is halogen, C₁-C₂alkyl or cyclopropyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is —CN, —Cl or—CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is —Cl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is substituted withone or more substituents selected from —OH, halogen, C₁-C₂ alkyl andalkylcarbonyloxy.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is substituted withone or more substituents selected from —F, methyl and —O—C(═O)—CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is substituted withtwo substituents that are the same or different.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XII) wherein R²⁵ is substituted withthree substituents that are the same or different.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein the compound is not

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein when L-Ar is

Ar is not

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl,

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²¹ is halogen, C₁-C₄alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²¹ is C₁-C₄ alkyl,C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²¹ is C₁-C₂ alkyl orC₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²¹ is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²¹ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²² is H or C₁-C₂alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²² is H or —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²² is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein each R²⁴ and R²⁵ isindependently H, —CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein each R²⁴ and R²⁵ isindependently H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-memberedheterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is H, C₁-C₄ alkyl,—(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is —CN, —Cl, C₁-C₄alkyl or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is C₁-C₄ alkyl or—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is —(C₁-C₂alkyl)-O—(C₁-C₂ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is C₁-C₄ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is substitutedwith one or more substituents selected from halogen, C₃-C₅ cycloalkyland C₁-C₂ alkoxy.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is substitutedwith one or more substituents selected from —F, cyclopropyl and —OCH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is substitutedwith two substituents that are the same or different.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁴ is substitutedwith three substituents that are the same or different.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is halogen,methyl, ethyl or cyclopropyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is —CN, —Cl, C₁-C₄alkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is —CN, —Cl, —CH₃,—O—(C₃-C₅ cycloalkyl) or —O—(C₁-C₂ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is —CN, —Cl orC₁-C₄ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is —Cl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is substitutedwith one or more halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is substitutedwith one or more —F.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is substituted bytwo substituents.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIII) wherein R²⁵ is substituted bythree substituents.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²¹ is halogen, C₁-C₄alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²¹ is H, C₁-C₄ alkyl,C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²¹ is C₁-C₂ alkyl orC₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²¹ is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²¹ is C₃-C₅cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²² is H or C₁-C₂alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²² is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²⁴ is C₁-C₄ alkyl or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIV) wherein R²⁴ is —(C₁-C₂alkyl)_(t)-O—(C₁-C₂ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R¹ is H, —CN, —C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl) wherein when R¹ is not H or —CN, R¹ is optionallysubstituted with one or more halogens.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R¹ is —CN or C₁-C₂haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R¹ is —Cl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R²¹ is halogen, C₁-C₄alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R²¹ is C₁-C₂ alkyl orC₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R²¹ is C₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R²² is H or C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein R²² is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein L³ is —N(CH₃)—.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein n is 2 and m is 2.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein n is 1 or 2.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XV) wherein n is 1 and m is 2.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVI) wherein L-Ar is

Ar is not

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVI) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVI) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVI) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVI) wherein R²¹ is halogen, C₁-C₄alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVI) wherein R²¹ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVI) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein L-Ar is

and Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²¹ is halogen, C₁-C₄alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²¹ is C₁-C₂ alkyl orC₃-C₅ cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²¹ is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²¹ is C₃-C₅cycloalkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²² is H or C₁-C₂alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²² is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²² is C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²² is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²⁴ is C₁-C₄ alkyl or—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVII) wherein R²⁴ is —(C₁-C₂alkyl)-O—(C₁-C₂ alkyl).

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVIII) wherein L-Ar is

Ar is not

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVIII) wherein L² is —NHR³⁵.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XVIII) wherein L² is —C(O)NHR³⁵¹.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIX) wherein Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIX) wherein Y is —CR²⁶— wherein R²⁶is —N(R²⁷)₂.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XIX) wherein X is —N—.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein the compound is not:

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein L-Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein L-Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein L-Ar is

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R³ is H.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R¹ is —CN or —O—(C₁-C₄alkyl), wherein when R¹ is not —CN, R¹ is optionally substituted withone or more halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R¹ is —CN.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R¹ is —O—(C₁-C₄ alkyl)optionally substituted with one or more halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein each R² is hydrogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R²¹ is C₁-C₄ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R²² is H or C₁-C₂ alkyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R²⁴ is —O—(C₁-C₄ alkyl)optionally substituted with one or more hydroxyl or halogen.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R²⁴ is —O—(C₁-C₄ alkyl)optionally substituted with one or more hydroxyl.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein R²⁵ is —CH₃.

In some embodiments of the methods above, the fatty acid synthaseinhibitor is a compound of Formula (XX) wherein the compound selectedfrom:

For aspects where a prophylactic benefit is desired, a pharmaceuticalcomposition of the invention can be administered to a patient at risk ofdeveloping viral infection such as HRV, or HIV, or to a patientreporting one or more of the physiological symptoms of a viralinfection, even though a diagnosis of the condition may not have beenmade. Administration can prevent the viral infection from developing, orit can reduce, lessen, shorten and/or otherwise ameliorate the viralinfection that develops. The pharmaceutical composition can modulate thefatty acid synthesis pathway, e.g., FASN gene expression or FASN proteinactivity. Wherein, the term modulate includes inhibition of the fattyacid synthesis pathway, e.g., FASN gene expression or FASN proteinactivity or alternatively activation of the fatty acid synthesispathway, e.g., FASN gene expression or FASN protein activity.

Reducing the activity of the fatty acid synthesis pathway, e.g., FASNgene expression or FASN protein activity, is also referred to as“inhibiting” the fatty acid synthesis pathway, e.g., FASN geneexpression or FASN protein activity. The term “inhibits” and itsgrammatical conjugations, such as “inhibitory,” do not require completeinhibition, but refer to a reduction in fatty acid synthesis activity,e.g., FASN gene expression or FASN protein activity. In another aspect,such reduction is by at least 50%, at least 75%, at least 90%, and canbe by at least 95% of the activity of the enzyme in the absence of theinhibitory effect, e.g., in the absence of an inhibitor. Conversely, thephrase “does not inhibit” and its grammatical conjugations refer tosituations where there is less than 20%, less than 10%, and can be lessthan 5%, of reduction in enzyme activity in the presence of the agent.Further the phrase “does not substantially inhibit” and its grammaticalconjugations refer to situations where there is less than 30%, less than20%, and in some aspects less than 10% of reduction in enzyme activityin the presence of the agent.

Increasing the activity of the fatty acid synthesis pathway, e.g., FASNgene expression or FASN protein activity, is also referred to as“activating” the fatty acid synthesis pathway, e.g., FASN geneexpression or FASN protein activity. The term “activated” and itsgrammatical conjugations, such as “activating,” do not require completeactivation, but refer to an increase in fatty acid synthesis pathwayactivity, e.g., FASN gene expression or FASN protein activity. Inanother aspect such increase is by at least 50%, at least 75%, at least90%, and can be by at least 95% of the activity of the enzyme in theabsence of the activation effect, e.g., in the absence of an activator.Conversely, the phrase “does not activate” and its grammaticalconjugations refer to situations where there is less than 20%, less than10%, and can be less than 5%, of an increase in enzyme activity in thepresence of the agent. Further the phrase “does not substantiallyactivate” and its grammatical conjugations refer to situations wherethere is less than 30%, less than 20%, and in another aspect less than10% of an increase in enzyme activity in the presence of the agent.

The ability to reduce enzyme activity is a measure of the potency or theactivity of an agent, or combination of agents, towards or against theenzyme. Potency can be measured by cell free, whole cell and/or in vivoassays in terms of IC50, K_(i) and/or ED50 values. An IC50 valuerepresents the concentration of an agent required to inhibit enzymeactivity by half (50%) under a given set of conditions. A K_(i) valuerepresents the equilibrium affinity constant for the binding of aninhibiting agent to the enzyme. An ED50 value represents the dose of anagent required to effect a half-maximal response in a biological assay.Further details of these measures will be appreciated by those ofordinary skill in the art, and can be found in standard texts onbiochemistry, enzymology, and the like.

The present invention also includes kits that can be used to treat viralinfections or treat cancer. These kits comprise an agent or combinationof agents that inhibit the fatty acid synthesis pathway, e.g., FASN geneexpression or FASN protein activity, and optionally instructionsteaching the use of the kit according to the various methods andapproaches described herein. Such kits can also include information,such as scientific literature references, package insert materials,clinical trial results, and/or summaries of these and the like, whichindicate or establish the activities and/or advantages of the agent.Such information can be based on the results of various studies, forexample, studies using experimental animals involving in vivo models andstudies based on human clinical trials. Kits described herein can beprovided, marketed and/or promoted to health providers, includingphysicians, nurses, pharmacists, formulary officials, and the like.

Formulations, Routes of Administration, and Effective Doses

Yet another aspect of the present invention relates to formulations,routes of administration and effective doses for pharmaceuticalcompositions comprising an agent or combination of agents of the instantinvention. Such pharmaceutical compositions can be used to treat viralinfections as described above.

Compounds of the invention can be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, transdermal patch, pulmonary,vaginal, suppository, or parenteral (including intramuscular,intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneousand intravenous) administration or in a form suitable for administrationby aerosolization, inhalation or insufflation. General information ondrug delivery systems can be found in Ansel et al., PharmaceuticalDosage Forms and Drug Delivery Systems (Uppencott Williams & Wilkins,Baltimore Md. (1999).

In various aspects, the pharmaceutical composition includes carriers andexcipients (including but not limited to buffers, carbohydrates,mannitol, proteins, polypeptides or amino acids such as glycine,antioxidants, bacteriostats, chelating agents, suspending agents,thickening agents and/or preservatives), water, oils including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like, saline solutions,aqueous dextrose and glycerol solutions, flavoring agents, coloringagents, detackifiers and other acceptable additives, adjuvants, orbinders, other pharmaceutically acceptable auxiliary substances asrequired to approximate physiological conditions, such as pH bufferingagents, tonicity adjusting agents, emulsifying agents, wetting agentsand the like. Examples of excipients include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. In another aspect, thepharmaceutical preparation is substantially free of preservatives. Inanother aspect, the pharmaceutical preparation can contain at least onepreservative. General methodology on pharmaceutical dosage forms isfound in Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It willbe recognized that, while any suitable carrier known to those ofordinary skill in the art can be employed to administer the compositionsof this invention, the type of carrier will vary depending on the modeof administration.

Compounds can also be encapsulated within liposomes using well-knowntechnology. Biodegradable microspheres can also be employed as carriersfor the pharmaceutical compositions of this invention. Suitablebiodegradable microspheres are disclosed, for example, in U.S. Pat. Nos.4,897,268; 5,075,109; 5,928,647; 5,811,128; 5,820,883; 5,853,763;5,814,344 and 5,942,252.

The compound can be administered in liposomes or microspheres (ormicroparticles). Methods for preparing liposomes and microspheres foradministration to a patient are well known to those of skill in the art.U.S. Pat. No. 4,789,734, the contents of which are hereby incorporatedby reference, describes methods for encapsulating biological materialsin liposomes. Essentially, the material is dissolved in an aqueoussolution, the appropriate phospholipids and lipids added, along withsurfactants if required, and the material dialyzed or sonicated, asnecessary. A review of known methods is provided by G. Gregoriadis,Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp.2.sup.87-341 (Academic Press, 1979).

Microspheres formed of polymers or proteins are well known to thoseskilled in the art, and can be tailored for passage through thegastrointestinal tract directly into the blood stream. Alternatively,the compound can be incorporated and the microspheres, or composite ofmicrospheres, implanted for slow release over a period of time rangingfrom days to months. See, for example, U.S. Pat. Nos. 4,906,474,4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contentsof which are hereby incorporated by reference.

The concentration of drug can be adjusted, the pH of the solutionbuffered and the isotonicity adjusted to be compatible with intravenousinjection, as is well known in the art.

The compounds of the invention can be formulated as a sterile solutionor suspension, in suitable vehicles, well known in the art. Thepharmaceutical compositions can be sterilized by conventional,well-known sterilization techniques, or can be sterile filtered. Theresulting aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterilesolution prior to administration. Suitable formulations and additionalcarriers are described in Remington “The Science and Practice ofPharmacy” (20^(th) Ed., Lippincott Williams & Wilkins, Baltimore Md.),the teachings of which are incorporated by reference in their entiretyherein.

The agents or their pharmaceutically acceptable salts can be providedalone or in combination with one or more other agents or with one ormore other forms. For example a formulation can comprise one or moreagents in particular proportions, depending on the relative potencies ofeach agent and the intended indication. For example, in compositions fortargeting two different host targets, and where potencies are similar,about a 1:1 ratio of agents can be used. The two forms can be formulatedtogether, in the same dosage unit e.g., in one cream, suppository,tablet, capsule, aerosol spray, or packet of powder to be dissolved in abeverage; or each form can be formulated in a separate unit, e.g., twocreams, two suppositories, two tablets, two capsules, a tablet and aliquid for dissolving the tablet, two aerosol sprays, or a packet ofpowder and a liquid for dissolving the powder, etc.

The term “pharmaceutically acceptable salt” means those salts whichretain the biological effectiveness and properties of the agents used inthe present invention, and which are not biologically or otherwiseundesirable. For example, a pharmaceutically acceptable salt does notinterfere with the beneficial effect of an agent of the invention ininhibiting the fatty acid synthesis pathway, e.g., inhibiting FASN geneexpression or FASN protein activity.

Typical salts are those of the inorganic ions, such as, for example,sodium, potassium, calcium, magnesium ions, and the like. Such saltsinclude salts with inorganic or organic acids, such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, mandelic acid, malic acid, citric acid,tartaric acid or maleic acid. In addition, if the agent(s) contain acarboxy group or other acidic group, it can be converted into apharmaceutically acceptable addition salt with inorganic or organicbases. Examples of suitable bases include sodium hydroxide, potassiumhydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine,diethanolamine, triethanolamine, and the like.

A pharmaceutically acceptable ester or amide refers to those whichretain biological effectiveness and properties of the agents used in thepresent invention, and which are not biologically or otherwiseundesirable. For example, the ester or amide does not interfere with thebeneficial effect of an agent of the invention in inhibiting the fattyacid synthesis pathway, e.g., inhibiting FASN gene expression or FASNprotein activity. Typical esters include ethyl, methyl, isobutyl,ethylene glycol, and the like. Typical amides include unsubstitutedamides, alkyl amides, dialkyl amides, and the like.

In another aspect, an agent can be administered in combination with oneor more other compounds, forms, and/or agents, e.g., as described above.Pharmaceutical compositions comprising combinations of a fatty acidsynthesis pathway inhibitor e.g., an inhibitor or FASN gene expressionor FASN protein activity with one or more other active agents can beformulated to comprise certain molar ratios. For example, molar ratiosof about 99:1 to about 1:99 of a fatty acid synthesis pathway inhibitore.g., an inhibitor of FASN gene expression or FASN protein activity, tothe other active agent can be used. In some subset of the aspects, therange of molar ratios of fatty acid synthesis pathway inhibitor e.g., aninhibitor of FASN gene expression or FASN protein activity: other activeagent is selected from about 80:20 to about 20:80; about 75:25 to about25:75, about 70:30 to about 30:70, about 66:33 to about 33:66, about60:40 to about 40:60; about 50:50; and about 90:10 to about 10:90. Themolar ratio of a fatty acid synthesis pathway inhibitor e.g., aninhibitor of FASN gene expression or FASN protein activity; other activeagent can be about 1:9, and in another aspect can be about 1:1. The twoagents, forms and/or compounds can be formulated together, in the samedosage unit e.g., in one cream, suppository, tablet, capsule, or packetof powder to be dissolved in a beverage; or each agent, form, and/orcompound can be formulated in separate units, e.g., two creams,suppositories, tablets, two capsules, a tablet and a liquid fordissolving the tablet, an aerosol spray a packet of powder and a liquidfor dissolving the powder, etc.

If necessary or desirable, the agents and/or combinations of agents canbe administered with still other agents. The choice of agents that canbe co-administered with the agents and/or combinations of agents of theinstant invention can depend, at least in part, on the condition beingtreated. Agents of particular use in the formulations of the presentinvention include, for example, any agent having a therapeutic effectfor a viral infection, including, e.g., drugs used to treat inflammatoryconditions. For example, in treatments for HRV, in some aspectsformulations of the instant invention can additionally contain one ormore conventional anti-inflammatory drugs, such as an NSAID, e.g.,ibuprofen, naproxen, acetaminophen, ketoprofen, or aspirin. In somealternative aspects for the treatment of influenza formulations of theinstant invention can additionally contain one or more conventionalinfluenza antiviral agents, such as amantadine, rimantadine, zanamivir,and oseltamivir. In treatments for retroviral infections, such as HIV,formulations of the instant invention can additionally contain one ormore conventional antiviral drug, such as protease inhibitors(lopinavir/ritonavir (Kaletra), indinavir (Crixivan), ritonavir(Norvir), nelfinavir (Viracept), saquinavir hard gel capsules(Invirase), atazanavir (Reyataz), amprenavir (Agenerase), fosamprenavir(Telzir), tipranavir (Aptivus)), reverse transcriptase inhibitors,including non-Nucleoside and Nucleoside/nucleotide inhibitors (AZT(zidovudine, Retrovir), ddI (didanosine, Videx), 3TC (lamivudine,Epivir), d4T (stavudine, Zerit), abacavir (Ziagen), FTC (emtricitabine,Emtriva), tenofovir (Viread), efavirenz (Sustiva) and nevirapine(Viramune)), fusion inhibitors T20 (enfuvirtide, Fuzeon), integraseinhibitors (MK-0518 and GS-9137), and maturation inhibitors (PA-457(Bevirimat)). As another example, formulations can additionally containone or more supplements, such as vitamin C, E or other anti-oxidants.

In certain aspects, the compounds of the present disclosure can beadministered in combination with a known cancer therapeutic. Forexample, the compounds can be administered in combination withpaclitaxel (commercially available as Taxol, Bristol-Myers Squibb),doxorubicin (also known under the trade name Adriamycin), vincristine(known under the trade names Oncovin, Vincasar PES, and Vincrex),actinomycin D, altretamine, asparaginase, bleomycin, busulphan,capecitabine, carboplatin, carmustine, chlorambucil, cisplatin,cyclophosphamide, cytarabine, dacarbazine, daunorubicin, epirubicin,etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea,idarubicin, ifosfamide, irinotecan, lomustine, melphalan,mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin,procarbazine, steroids, streptozocin, taxotere, tzunozolomide,thioguanine, thiotepa, tomudex, topotecan, treosulfan, UFT(uracil-tegufur), vinblastine, and vindesine, or the like.

The agent(s) (or pharmaceutically acceptable salts, esters or amidesthereof) can be administered per se or in the form of a pharmaceuticalcomposition wherein the active agent(s) is in an admixture or mixturewith one or more pharmaceutically acceptable carriers. A pharmaceuticalcomposition, as used herein, can be any composition prepared foradministration to a subject. Pharmaceutical compositions for use inaccordance with the present invention can be formulated in conventionalmanner using one or more physiologically acceptable carriers, comprisingexcipients, diluents, and/or auxiliaries, e.g., which facilitateprocessing of the active agents into preparations that can beadministered. Proper formulation can depend at least in part upon theroute of administration chosen. The agent(s) useful in the presentinvention, or pharmaceutically acceptable salts, esters, or amidesthereof, can be delivered to a patient using a number of routes or modesof administration, including oral, buccal, topical, rectal, transdermal,transmucosal, subcutaneous, intravenous, and intramuscular applications,as well as by inhalation.

For oral administration, the agents can be formulated readily bycombining the active agent(s) with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the agents of the inventionto be formulated as tablets, including chewable tablets, pills, dragees,capsules, lozenges, hard candy, liquids, gels, syrups, slurries,powders, suspensions, elixirs, wafers, and the like, for oral ingestionby a patient to be treated. Such formulations can comprisepharmaceutically acceptable carriers including solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents. Asolid carrier can be one or more substances which can also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Generally, the agents of the invention will be included at concentrationlevels ranging from about 0.5%, about 5%, about 10%, about 20%, or about30% to about 50%, about 60%, about 70%, about 80% or about 90% by weightof the total composition of oral dosage forms, in an amount sufficientto provide a desired unit of dosage.

Aqueous suspensions for oral use can contain agent(s) of this inventionwith pharmaceutically acceptable excipients, such as a suspending agent(e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithinand/or a long-chain fatty alcohol), as well as coloring agents,preservatives, flavoring agents, and the like.

In another aspect, oils or non-aqueous solvents can be required to bringthe agents into solution, due to, for example, the presence of largelipophilic moieties. Alternatively, emulsions, suspensions, or otherpreparations, for example, liposomal preparations, can be used. Withrespect to liposomal preparations, any known methods for preparingliposomes for treatment of a condition can be used. See, for example,Bangham et al., J. Mol. Biol. 23: 238-252. (1965) and Szoka et at.,Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein byreference. Ligands can also be attached to the liposomes to direct thesecompositions to particular sites of action. Agents of this invention canalso be integrated into foodstuffs, e.g., cream cheese, butter, saladdressing, or ice cream to facilitate solubilization, administration,and/or compliance in certain patient populations.

Pharmaceutical preparations for oral use can be obtained as a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; flavoring elements, cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone (PVP). If desired, disintegrating agents can beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate: The agents can also beformulated as a sustained release preparation.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active agents can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions canbe prepared in solutions, for example, in aqueous propylene glycolsolutions or can contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell-known suspending agents. Suitable fillers or carriers with whichthe compositions can be administered include agar, alcohol, fats,lactose, starch, cellulose derivatives, polysaccharides,polyvinylpyrrolidone, silica, sterile saline and the like, or mixturesthereof used in suitable amounts. Solid form preparations includesolutions, suspensions, and emulsions, and can contain, in addition tothe active component, colorants, flavors, stabilizers, buffers,artificial and natural sweeteners, dispersants, thickeners, solubilizingagents, and the like.

A syrup or suspension can be made by adding the active compound to aconcentrated, aqueous solution of a sugar, e.g., sucrose, to which canalso be added any accessory ingredients. Such accessory ingredients caninclude flavoring, an agent to retard crystallization of the sugar or anagent to increase the solubility of any other ingredient, e.g., as apolyhydric alcohol, for example, glycerol or sorbitol.

When formulating compounds of the invention for oral administration, itcan be desirable to utilize gastroretentive formulations to enhanceabsorption from the gastrointestinal (GI) tract. A formulation which isretained in the stomach for several hours can release compounds of theinvention slowly and provide a sustained release that can be used inmethods of the invention. Disclosure of such gastro-retentiveformulations are found in Klausner, E. A.; Lavy, E.; Barta, M.;Cserepes, E.; Friedman, M.; Hoffman, A. 2003 “Novel gastroretentivedosage forms: evaluation of gastroretentivity and its effect on levodopain humans.” Pharm. Res. 20, 1466-73, Hoffman, A.; Stepensky, D.; Lavy,E.; Eyal, S. Klausner, E.; Friedman, M. 2004 “Pharmacokinetic andpharmacodynamic aspects of gastroretentive dosage forms” Int. J. Pharm.11, 141-53, Streubel, A.; Siepmann, J.; Bodmeier, R.; 2006“Gastroretentive drug delivery systems” Exp. Opin. Drug Deliver. 3,217-3, and Chavanpatil, M. D.; Jain, P.; Chaudhari, S.; Shear, R.;Vavia, P. R. “Novel sustained release, swellable and bioadhesivegastroretentive drug delivery system for olfoxacin” Int. J. Pharm. 2006epub March 24. Expandable, floating and bioadhesive techniques can beutilized to maximize absorption of the compounds of the invention.

The compounds of the invention can be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and can be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions can take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol.

For injectable formulations, the vehicle can be chosen from those knownin art to be suitable, including aqueous solutions or oil suspensions,or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil,as well as elixirs, mannitol, dextrose, or a sterile aqueous solution,and similar pharmaceutical vehicles. The formulation can also comprisepolymer compositions which are biocompatible, biodegradable, such aspolylactic-co-glycolic)acid. These materials can be made into micro ornanospheres, loaded with drug and further coated or derivatized toprovide superior sustained release performance. Vehicles suitable forperiocular or intraocular injection include, for example, suspensions oftherapeutic agent in injection grade water, liposomes and vehiclessuitable for lipophilic substances. Other vehicles for periocular orintraocular injection are well known in the art.

In a preferred aspect, the composition is formulated in accordance withroutine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition can also include a solubilizingagent and a local anesthetic such as lidocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

When administration is by injection, the active compound can beformulated in aqueous solutions, specifically in physiologicallycompatible buffers such as Hanks solution, Ringer's solution, orphysiological saline buffer. The solution can contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the active compound can be in powder form for constitution with asuitable vehicle, e.g., sterile pyrogen-free water, before use. Inanother aspect, the pharmaceutical composition does not comprise anadjuvant or any other substance added to enhance the immune responsestimulated by the peptide. In another aspect, the pharmaceuticalcomposition comprises a substance that inhibits an immune response tothe peptide. Methods of formulation are known in the art, for example,as disclosed in Remington's Pharmaceutical Sciences, latest edition,Mack Publishing Co., Easton P.

In addition to the formulations described previously, the agents canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation or transcutaneous delivery (forexample subcutaneously or intramuscularly), intramuscular injection oruse of a transdermal patch. Thus, for example, the agents can beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

In another aspect, pharmaceutical compositions comprising one or moreagents of the present invention exert local and regional effects whenadministered topically or injected at or near particular sites ofinfection. Direct topical application, e.g., of a viscous liquid,solution, suspension, dimethylsulfoxide (DMSO)-based solutions,liposomal formulations, gel, jelly, cream, lotion, ointment,suppository, foam, or aerosol spray, can be used for localadministration, to produce for example local and/or regional effects.Pharmaceutically appropriate vehicles for such formulation include, forexample, lower aliphatic alcohols, poly glycols (e.g., glycerol orpolyethylene glycol), esters of fatty acids, oils, fats, silicones, andthe like. Such preparations can also include preservatives (e.g.,p-hydroxybenzoic acid esters) and/or antioxidants (e.g., ascorbic acidand tocopherol). See also Dermatological Formulations: Percutaneousabsorption, Barry (Ed.), Marcel Dekker Incl, 1983. In another aspect,local/topical formulations comprising a fatty acid synthesis pathwayinhibitor e.g., an inhibitor of FASN gene expression or FASN proteinactivity, are used to treat epidermal or mucosal viral infections.

Pharmaceutical compositions of the present invention can contain acosmetically or dermatologically acceptable carrier. Such carriers arecompatible with skin, nails, mucous membranes, tissues and/or hair, andcan include any conventionally used cosmetic or dermatological carriermeeting these requirements. Such carriers can be readily selected by oneof ordinary skill in the art. In formulating skin ointments, an agent orcombination of agents of the instant invention can be formulated in anoleaginous hydrocarbon base, an anhydrous absorption base, awater-in-oil absorption base, an oil-in-water water-removable baseand/or a water-soluble base. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Ointments and creams can, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions can be formulated with an aqueous or oily base and willin general also containing one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

The compositions according to the present invention can be in any formsuitable for topical application, including aqueous, aqueous-alcoholicor oily solutions, lotion or serum dispersions, aqueous, anhydrous oroily gels, emulsions obtained by dispersion of a fatty phase in anaqueous phase (O/W or oil in water) or, conversely, (W/O or water inoil), microemulsions or alternatively microcapsules, microparticles orlipid vesicle dispersions of ionic and/or nonionic type. Thesecompositions can be prepared according to conventional methods. Otherthan the agents of the invention, the amounts of the variousconstituents of the compositions according to the invention are thoseconventionally used in the art. These compositions in particularconstitute protection, treatment or care creams, milks, lotions, gels orfoams for the face, for the hands, for the body and/or for the mucousmembranes, or for cleansing the skin. The compositions can also consistof solid preparations constituting soaps or cleansing bars.

Compositions of the present invention can also contain adjuvants commonto the cosmetic and dermatological fields, such as hydrophilic orlipophilic gelling agents, hydrophilic or lipophilic active agents,preserving agents, antioxidants, solvents, fragrances, fillers,sunscreens, odor-absorbers and dyestuffs. The amounts of these variousadjuvants are those conventionally used in the fields considered and,for example, are from about 0.01% to about 20% of the total weight ofthe composition. Depending on their nature, these adjuvants can beintroduced into the fatty phase, into the aqueous phase and/or into thelipid vesicles.

In another aspect, ocular viral infections can be effectively treatedwith ophthalmic solutions, suspensions, ointments or inserts comprisingan agent or combination of agents of the present invention. Eye dropscan be prepared by dissolving the active ingredient in a sterile aqueoussolution such as physiological saline, buffering solution, etc., or bycombining powder compositions to be dissolved before use. Other vehiclescan be chosen, as is known in the art, including but not limited to:balance salt solution, saline solution, water soluble polyethers such aspolyethyene glycol, polyvinyls, such as polyvinyl alcohol and povidone,cellulose derivatives such as methylcellulose and hydroxypropylmethylcellulose, petroleum derivatives such as mineral oil and whitepetrolatum, animal fats such as lanolin, polymers of acrylic acid suchas carboxypolymethylene gel, vegetable fats such as peanut oil andpolysaccharides such as dextrans, and glycosaminoglycans such as sodiumhyaluronate. If desired, additives ordinarily used in the eye drops canbe added. Such additives include isotonizing agents (e.g., sodiumchloride, etc.), buffer agent (e.g., boric acid, sodium monohydrogenphosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g.,benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.),thickeners (e.g., saccharide such as lactose, mannitol, maltose, etc.;e.g., hyaluronic acid or its salt such as sodium hyaluronate, potassiumhyaluronate, etc.; e.g., mucopolysaccharide such as chondroitin sulfate,etc.; e.g., sodium polyacrylate, carboxyvinyl polymer, crosslinkedpolyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose,carboxymethyl cellulose, hydroxy propyl cellulose or other agents knownto those skilled in the art).

The solubility of the components of the present compositions can beenhanced by a surfactant or other appropriate co-solvent in thecomposition. Such cosolvents include polysorbate 20, 60, and 80,Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known tothose skilled in the art. Such co-solvents can be employed at a level offrom about 0.01% to by weight.

The compositions of the invention can be packaged in multidose form.Preservatives can be preferred to prevent microbial contamination duringuse. Suitable preservatives include: benzalkonium chloride, thimerosal,chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,edetate disodium, sorbic acid, Onamer M, or other agents known to thoseskilled in the art. In the prior art ophthalmic products, suchpreservatives can be employed at a level of from 0.004% to 0.02%. In thecompositions of the present application the preservative, preferablybenzalkonium chloride, can be employed at a level of from 0.001% to lessthan 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% byweight. It has been found that a concentration of benzalkonium chlorideof 0.005% can be sufficient to preserve the compositions of the presentinvention from microbial attack.

In another aspect, viral infections of the ear can be effectivelytreated with otic solutions, suspensions, ointments or insertscomprising an agent or combination of agents of the present invention.

In another aspect, the agents of the present invention are delivered insoluble rather than suspension form, which allows for more rapid andquantitative absorption to the sites of action. In general, formulationssuch as jellies, creams, lotions, suppositories and ointments canprovide an area with more extended exposure to the agents of the presentinvention, while formulations in solution, e.g., sprays, provide moreimmediate, short-term exposure.

In another aspect relating to topical/local application, thepharmaceutical compositions can include one or more penetrationenhancers. For example, the formulations can comprise suitable solid orgel phase carriers or excipients that increase penetration or helpdelivery of agents or combinations of agents of the invention across apermeability barrier, e.g., the skin. Many of thesepenetration-enhancing compounds are known in the art of topicalformulation, and include, e.g., water, alcohols (e.g., terpenes likemethanol, ethanol, 2-propanol), sulfoxides (e.g., dimethyl sulfoxide,decylmethyl sulfoxide, tetradecylmethyl sulfoxide), pyrrolidones (e.g.,2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone),laurocapram, acetone, dimethylacetamide, dimethylformamide,tetrahydrofurfuryl alcohol, L-α-amino acids, anionic, cationic,amphoteric or nonionic surfactants (e.g., isopropyl myristate and sodiumlauryl sulfate), fatty acids, fatty alcohols (e.g., oleic acid),amities, amides, clofibric acid amides, hexamethylene lauramide,proteolytic enzymes, α-bisabolol, d-limonene, urea andN,N-diethyl-m-toluamide, and the like. Additional examples includehumectants (e.g., urea), glycols (e.g., propylene glycol andpolyethylene glycol), glycerol monolaurate, alkanes, alkanols, ORGELASE,calcium carbonate, calcium phosphate, various sugars, starches,cellulose derivatives, gelatin, and/or other polymers. In anotheraspect, the pharmaceutical compositions will include one or more suchpenetration enhancers.

In another aspect, the pharmaceutical compositions for local/topicalapplication can include one or more antimicrobial preservatives such asquaternary ammonium compounds, organic mercurials, p-hydroxy benzoates,aromatic alcohols, chlorobutanol, and the like.

Gastrointestinal viral infections can be effectively treated withorally- or rectally delivered solutions, suspensions, ointments, enemasand/or suppositories comprising an agent or combination of agents of thepresent invention.

Respiratory viral infections can be effectively treated with aerosolsolutions, suspensions or dry powders comprising an agent or combinationof agents of the present invention. Administration by inhalation isparticularly useful in treating viral infections of the lung, such as anHRV infection. The aerosol can be administered through the respiratorysystem or nasal passages. For example, one skilled in the art willrecognize that a composition of the present invention can be suspendedor dissolved in an appropriate carrier, e.g., a pharmaceuticallyacceptable propellant, and administered directly into the lungs using anasal spray or inhalant. For example, an aerosol formulation comprisinga fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN geneexpression or FASN protein activity, can be dissolved, suspended oremulsified in a propellant or a mixture of solvent and propellant, e.g.,for administration as a nasal spray or inhalant. Aerosol formulationscan contain any acceptable propellant under pressure, such as acosmetically or dermatologically or pharmaceutically acceptablepropellant, as conventionally used in the art.

An aerosol formulation for nasal administration is generally an aqueoussolution designed to be administered to the nasal passages in drops orsprays. Nasal solutions can be similar to nasal secretions in that theyare generally isotonic and slightly buffered to maintain a pH of about5.5 to about 6.5, although pH values outside of this range canadditionally be used. Antimicrobial agents or preservatives can also beincluded in the formulation.

An aerosol formulation for inhalations and inhalants can be designed sothat the agent or combination of agents of the present invention iscarried into the respiratory tree of the subject when administered bythe nasal or oral respiratory route. Inhalation solutions can beadministered, for example, by a nebulizer. Inhalations or insufflations,comprising finely powdered or liquid drugs, can be delivered to therespiratory system as a pharmaceutical aerosol of a solution orsuspension of the agent or combination of agents in a propellant, e.g.,to aid in disbursement. Propellants can be liquefied gases, includinghalocarbons, for example, fluorocarbons such as fluorinated chlorinatedhydrocarbons, hydrochlorofluorocarbons, and hydrochlorocarbons, as wellas hydrocarbons and hydrocarbon ethers.

Halocarbon propellants useful in the present invention includefluorocarbon propellants in which all hydrogens are replaced withfluorine, chlorofluorocarbon propellants in which all hydrogens arereplaced with chlorine and at least one fluorine, hydrogen-containingfluorocarbon propellants, and hydrogen-containing chlorofluorocarbonpropellants. Halocarbon propellants are described in Johnson, U.S. Pat,No. 5,376,359, issued Dec. 27, 1994; Byron et al., U.S. Pat. No.5,190,029, issued Mar. 2, 1993; and Purewal et al., U.S. Pat. No.5,776,434, issued Jul. 7, 1998. Hydrocarbon propellants useful in theinvention include, for example, propane, isobutane, n-butane, pentane,isopentane and neopentane. A blend of hydrocarbons can also be used as apropellant. Ether propellants include, for example, dimethyl ether aswell as the ethers. An aerosol formulation of the invention can alsocomprise more than one propellant. For example, the aerosol formulationcan comprise more than one propellant from the same class, such as twoor more fluorocarbons; or more than one, more than two, more than threepropellants from different classes, such as a fluorohydrocarbon and ahydrocarbon. Pharmaceutical compositions of the present invention canalso be dispensed with a compressed gas, e.g., an inert gas such ascarbon dioxide, nitrous oxide or nitrogen.

Aerosol formulations can also include other components, for example,ethanol, isopropanol, propylene glycol, as well as surfactants or othercomponents such as oils and detergents. These components can serve tostabilize the formulation and/or lubricate valve components.

The aerosol formulation can be packaged under pressure and can beformulated as an aerosol using solutions, suspensions, emulsions,powders and semisolid preparations. For example, a solution aerosolformulation can comprise a solution of an agent of the invention such asa fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN geneexpression or FASN protein activity, in (substantially) pure propellantor as a mixture of propellant and solvent. The solvent can be used todissolve the agent and/or retard the evaporation of the propellant.Solvents useful in the invention include, for example, water, ethanoland glycols. Any combination of suitable solvents can be use, optionallycombined with preservatives, antioxidants, and/or other aerosolcomponents.

An aerosol formulation can also be a dispersion or suspension. Asuspension aerosol formulation can comprise a suspension of an agent orcombination of agents of the instant invention, e.g., a fatty acidsynthesis pathway inhibitor, e.g., an inhibitor of FASN gene expressionor FASN protein activity, and a dispersing agent. Dispersing agentsuseful in the invention include, for example, sorbitan trioleate, oleylalcohol, oleic acid, lecithin and corn oil. A suspension aerosolformulation can also include lubricants, preservatives, antioxidant,and/or other aerosol components.

An aerosol formulation can similarly be formulated as an emulsion. Anemulsion aerosol formulation can include, for example, an alcohol suchas ethanol, a surfactant, water and a propellant, as well as an agent orcombination of agents of the invention, e.g., a fatty acid synthesispathway, e.g., an inhibitor of FASN gene expression or FASN proteinactivity. The surfactant used can be nonionic, anionic or cationic. Oneexample of an emulsion aerosol formulation comprises, for example,ethanol, surfactant, water and propellant. Another example of anemulsion aerosol formulation comprises, for example, vegetable oil,glyceryl monostearate and propane.

The compounds of the invention can be formulated for administration assuppositories. A low melting wax, such as a mixture of triglycerides,fatty acid glycerides, Witepsol S55 (trademark of Dynamite NobelChemical, Germany), or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the invention can be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

It is envisioned additionally, that the compounds of the invention canbe attached releasably to biocompatible polymers for use in sustainedrelease formulations on, in or attached to inserts for topical,intraocular, periocular, or systemic administration. The controlledrelease from a biocompatible polymer can be utilized with a watersoluble polymer to form a instillable formulation, as well. Thecontrolled release from a biocompatible polymer, such as for example,PLGA microspheres or nanospheres, can be utilized in a formulationsuitable for intra ocular implantation or injection for sustainedrelease administration, as well. Any suitable biodegradable andbiocompatible polymer can be used.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are present in aneffective amount, i.e., in an amount effective to achieve therapeuticand/or prophylactic benefit in a host with at least one viral infectionor in a subject having cancer. The actual amount effective for aparticular application will depend on the condition or conditions beingtreated, the condition of the subject, the formulation, and the route ofadministration, as well as other factors known to those of skill in theart. Determination of an effective amount of a fatty acid synthesispathway inhibitor e.g., an inhibitor of FASN gene expression or FASNprotein activity, is well within the capabilities of those skilled inthe art, in light of the disclosure herein, and will be determined usingroutine optimization techniques.

The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievecirculating, liver, topical and/or gastrointestinal concentrations thathave been found to be effective in animals. One skilled in the art candetermine the effective amount for human use, especially in light of theanimal model experimental data described herein. Based on animal data,and other types of similar data, those skilled in the art can determinethe effective amounts of compositions of the present inventionappropriate for humans.

The effective amount when referring to an agent or combination of agentsof the invention will generally mean the dose ranges, modes ofadministration, formulations, etc., that have been recommended orapproved by any of the various regulatory or advisory organizations inthe medical or pharmaceutical arts (e.g., FDA, AMA) or by themanufacturer or supplier.

Further, appropriate doses for a fatty acid synthesis pathway inhibitore.g., an inhibitor of FASN gene expression or FASN protein activity, canbe determined based on in vitro experimental results. For example, thein vitro potency of an agent in inhibiting a fatty acid synthesispathway component, e.g., FASN gene expression or FASN protein activity,provides information useful in the development of effective in vivodosages to achieve similar biological effects.

In another aspect, administration of agents of the present invention canbe intermittent, for example administration once every two days, everythree days, every five days, once a week, once or twice a month, and thelike. In another aspect, the amount, forms, and/or amounts of thedifferent forms can be varied at different times of administration.

A person of skill in the art would be able to monitor in a patient theeffect of administration of a particular agent. For example, HIV viralload levels can be determined by techniques standard in the art, such asmeasuring CD4 cell counts, and/or viral levels as detected by PCR. Othertechniques would be apparent to one of skill in the art.

Having now generally described various aspects and aspects of theinvention, the same will be more readily understood through reference tothe following examples which are provided by way of illustration, andare not intended to be limiting, unless specified.

EXAMPLES Example Synthesis of Compounds of the Present Disclosure

General: All reactions and manipulations described were carried out inwell ventilated fume-hoods. Operations and reactions carried out atelevated or reduced pressure were carried out behind blast shields.Abbreviations: ACN, acetonitrile; AcOH, acetic acid; AIBN,azobisisobutyronitrile; BuLi, butyl lithium; CDI,1,1′-Carbonyldiimidazole; DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCE,1,2-dichloroethane; DCM, dichloromethane or methylene chloride; DIEA,N,N-Diisopropylethylamine; DMAP, 4-dimethylaminopyridine; DMF,N,N-dimethylformamide; DMSO, dimethylsulfoxide; EDC,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EtOAc,ethyl acetate; EtOH, Ethanol; HATU,2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate; HBTU,O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate or2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate; HMPA, hexamethylphosphoramide; HOAc, acetic acid;HOBT, 1-Hydroxybenzotriazole; LDA, lithium diisopropylamine; MeOH,methanol; MsCl, methanesulfonyl chloride; MsOH, methanesulfonic acid;NBS, N-bromosuccinimide; NIS, N-iodosuccinitnide; PE, petroleum ether;PTAT, phenyltrimethylammonium tribromide; PTSA, p-toluenesulfonic acid;Py, pyridine; Pyr, pyridine; TEA, triethylamine; TEA, trifluoroaceticacid; THF, tetrahydrofuran; TMSCl, chlorotrimethylsilane; TsOH,p-toluenesulfonic acid.

Compound 1.1. tert-Butyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate. To a stirredsolution of 1-bromo-4-iodobenzene (93.7 g, 331.21 mmol, 1.10 equiv) intetrahydrofuran (800 mL) under nitrogen at −78° C. was added dropwise ofa solution of butyllithium (150 mL, 2.43 M in THF, 1.05 equiv) during 30min. The resulting solution was stirred for 2 h at −78° C. To this wasthen added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (60 g,301.13 mmol, 1.00 equiv) in tetrahydrofuran (800 mL) dropwise withstirring at −78° C. during 30 min. After stirring for 1 h at −78° C.,reaction was carefully quenched with 350 mL of H₂O. The resultingmixture was extracted with 2×400 mL of ethyl acetate and the combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:200-1:10) as eluentto yield 91 g (85%) of the title compound as a yellow oil.

Compound 1.2. tert-Butyl4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate. A solution oftert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound1.1, 36 g, 101.05 mmol, 1.00 equiv), Pd(PPh₃)₄ (11.7 g, 10.12 mmol, 0,05equiv), and Zn(CN)₂ (17.9 g, 152.44 mmol, 1.51 equiv) in DMF (400 mL)under nitrogen was stirred overnight at 80° C. After reaching ambienttemperature, the reaction was then quenched by the addition of 600 mL ofFeSO₄ (aq., sat.) and diluted with ethyl acetate. The resulting mixturewas stirred vigorously then filtered through celite and washed with 1 MFeSO₄, water, and ethyl acetate. The layers were separated and theaqueous phase was extracted with 2×300 mL of ethyl acetate. The combinedorganic layers were washed with 1×200 mL of potassium carbonate (aq.,sat.) followed by 1×200 mL of brine, dried (Na₂SO₄), and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:200-1:5) as eluentto yield 23 g (75%) of the title compound as a white solid.

Compound 1.3. tert-Butyl 4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate. Into a round-bottom flask, was placed a solution oftert-butyl 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (compound1.2, 2. g, 6.61 mmol, 1.00 equiv) in pyridine (40 mL). POCl₃ (10.16 g,66.26 mmol, 10.02. equiv) was carefully added. The resulting mixture wasstirred under nitrogen overnight at room temperature and thenconcentrated under vacuum. The residue was taken up in 20 mL of DCM,washed with 2×20 mL of sodium bicarbonate (aq), dried (Na₂SO₄), andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with PE/EtOAc (100:1-30:1) as eluent toyield 1.4 g (74%) of the title compound as a white solid.

Compound 1.4. tert-Butyl 4-(4-cyanophenyl)piperidine-1-carboxylate.Around-bottom flask, containing a solution of tert-butyl4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 1.3,500 mg, 1.76 mmol, 1.00 equiv) in ethyl acetate (20 mL) was purged withnitrogen gas. To the solution was then added palladium on carbon (0.1 g,10%, 60% water) and the flask was then further purged with nitrogen. Theatmosphere was then changed to hydrogen and the mixture was stirredovernight at room temperature. After purging the system with nitrogen,the solids were removed by filtration and the filtrate was concentratedunder reduced pressure to yield 0.2 g (40%) of the title compound as ayellow oil.

Compound 1.5. 4-(Piperidin-4-yl)benzonitrile hydrochloride. Into a100-mL, 3-necked round-bottom flask, was placed a solution of tert-butyl4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.4, 4 g, 13.99mmol, 1.00 equiv) in ethyl acetate (60 mL). Hydrogen chloride (gas) wasbubbled through the solution and the resulting mixture was stirred for 1h at room temperature. The formed precipitate was collected byfiltration and dried to yield 2.2 g (71%) of the title compound as awhite solid. m/z (ES+) 187 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.72 (d,J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 3.54 (d with fine structure,J=12.6 Hz, 2H), 3.18 (t with fine structure, J=12.2 Hz, 2H), 3.12-1.97(m, 1H), 2.11 (d with fine structure, J=14.1 Hz, 2H), 2.04-1.84 (m, 2H).

Compound 1.6. Methyl 3-bromo-4-methylbenzoate. A solution of3-bromo-4-methylbenzoic acid (20 g, 93.00 mmol, 1.00 equiv) and sulfuricacid (20 mL) in methanol (100 mL) was stirred overnight at 80° C. Themixture was then concentrated under reduced pressure and the residue wasdiluted with 500 mL of ethyl acetate. The resulting mixture was washedwith 3×200 mL of water, 1×200 mL of sodium bicarbonate (aq), followed by1×200 mL of brine. The organic phase was dried over anhydrous sodiumsulfate, concentrated under reduced pressure, and dried to yield 20 g(94%) of the title compound as a dark red oil.

Compound 1.7. Methyl 3-cyano-4-methylbenzoate. A mixture of methyl3-bromo-4-methylbenzoate (compound 1.6, 18 g, 78.58 mmol, 1.00 equiv),Zn(CN)₂ (11.1 g, 94.87 mmol, 1.20 equiv), and Pd(PPh₃)₄ (7.3 g, 6.32mmol, 0.08 equiv) in N,N-dimethylformamide (250 mL) was stirred under anitrogen atmosphere at 100° C. overnight. After cooling to roomtemperature, the reaction was then quenched by careful addition of 200mL of FeSO₄(aq., sat.) and diluted with ethyl acetate. The resultingmixture was stirred vigorously then filtered through celite and washedwith 1 M FeSO₄, water, and ethyl acetate. The layers were separated andthe aqueous phase was extracted with 2×500 mL of ethyl acetate. Thecombined organic layers were washed with 3×200 mL of brine, dried overNa₂SO₄), and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:50) as eluent to yield 11 g (76%) of thetitle compound as an off-white solid.

Compound 1.8. Methyl 3-(N′-hydroxycarbamimidoyl)-4-methylbenzoate. Amixture of methyl 3-cyano-4-methylbenzoate (compound 1.7, 8 g, 43.38mmol, 1.00 equiv, 95%), NH₂OH.HCl (3.785 g, 54.86 mmol, 1.20 equiv), andN,N-Diisopropylethylamine (DIEA, 17.7 g, 136.95 mmol, 3.00 equiv) intetrahydrofuran (100 mL) was stirred overnight at 70° C. After coolingto room temperature, the mixture was concentrated under reducedpressure. The residue was taken up in water and the pH was adjusted to2-3 with hydrogen chloride (aqueous, 1 M). After washing the mixturewith 3×40 mL of ethyl acetate, the pH of the aqueous layer was adjustedto 8-9 with NaOH (aqueous, 2 M) followed by extraction with 3×30 mL ofethyl acetate. The combined organic layers were dried over (Na₂SO₄) andconcentrated under reduced pressure to yield 2.76 g (29%) of the titlecompound as a white solid.

Compound 1.9. Methyl 3-carbamimidoyl-4-methylbenzoate. A round-bottomflask, containing a solution of methyl3-(N-hydroxycarbamimidoyl)-4-methylbenzoate (compound 1.8, 8 g, 36.50mmol, 1.00 equiv, 95%) in methanol (150 mL) was purged with nitrogengas. To the solution was added palladium on carbon (9 g, 10%, 60% water)and the flask was then further purged with nitrogen gas. The atmospherewas then changed to hydrogen and the mixture was stirred overnight at25° C. under a balloon. After purging the system with nitrogen, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure to yield 4 g (54%) of the title compound as abrown solid.

Compound 1.10.1 3-Bromodihydro-2H-pyran-4(3H)-one. To a mixture ofdihydro-2H-pyran-4(3H)-one (10 g, 99.88 mmol, 1.00 equiv) and NH₄OAc(3.56 g, 46.23 mmol) in tetrahydrofuran (100 mL) at 0° C. under nitrogenwas added in several batches N-bromosuccinimide (17.8 g, 100.00 mmol,1.00 equiv). The resulting mixture was stirred overnight at 30° C. undernitrogen. The reaction mixture was then filtered and the filtrate wasconcentrated. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1/10-1/5) as eluentto yield 15 g (50%) of the title compound as a brown oil.

Compound 1.10. Methyl4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate. Amixture of methyl 3-carbamimidoyl-4-methylbenzoate (compound 1.9, 400mg, 1.98 mmol, 1.00 equiv, 95%), 3-bromodihydro-2H-pyran-4(3H)-one(compound 1.10.1, 750 mg, 2.09 mmol, 1.00 equiv), and potassiumcarbonate (580 mg, 4.20 mmol, 2.00 equiv) in CH₃CN (15 mL) was stirredovernight at 80° C. under nitrogen. After cooling to ambienttemperature, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in 50 mL of ethyl acetate and washedwith 2×10 mL of H₂O. The organic phase was dried over (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography and purified using ethylacetate/petroleum ether (1/3) to yield 0.21 g (37%) of the titlecompound as a white solid.

Compound 1.11.4-Methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid. Amixture of methyl4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate(compound 1.10, 210 mg, 0.73 mmol, 1.00 equiv, 95%) and sodium hydroxide(92.65 mg, 2.32 mmol, 3.00 equiv) in 12 mL methanol/H₂O (2:1) wasstirred for at 60° C. in an oil bath. After 2 h, the reaction mixturewas concentrated under reduced pressure and the residue was taken up in5 mL of H₂O. The resulting mixture was washed with 3×10 mL of ethylacetate and the pH of the aqueous layer was then adjusted to 2-3 usinghydrogen chloride (aq., 2 M). The resulting mixture was extracted with3×30 mL of ethyl acetate. The combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure to yield 0.21 g (89%)of the title compound as a white solid.

Compound 1. Methyl 4-(1-(4-methyl-3-(34,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.A mixture of4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid(compound 1.11, 60 mg, 0.22 mmol, 1.00 equiv, 95%), EDCI (88.4 mg, 0.46mmol, 2.00 equiv), DMAP (85.12 mg, 0.70 mmol, 3.00 equiv), and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 52 mg, 0.23mmol, 1.00 equiv) in DMF was stirred at room temperature. After 3 h, thereaction mixture was diluted with 40 mL of DCM and washed with 2×10 mLof NH₄Cl (aq. sat.) followed by 2×10 mL of brine. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct (˜100 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006 (Waters)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH3CN (15.0% CH3CN up to42.0% in 12 min, up to 100.0% in 1 min); Detector, uv 254/220 nm. Thefractions containing pure compound were combined and lyophilized toyield 32.9 mg (34%) of the title compound as a white solid. m/z (ES+)427 (M+H)⁻. ¹H NMR (300 MHz, CD₃OD): δ 7.73-7.65 (m, 4H), 7.61 (d, J=5.7Hz, 1H), 7.50 (d, J=6.0 Hz, 2H), 4.89-4.78 (1H partially obscured bywater peak), 4.81 (s, 2H), 4.10 (t, J=4.1 Hz, 2H), 3.94-3.81 (m, 1H),˜3.35 (1H partially obscured by methanol solvent peak), 3.08-1.95 (m,2H), 2.92 (t, J=4.1 Hz, 2H), 2.52 (s, 3H), 2.08-192 (m, 1H), 1.92-1.65(m, 3H). ¹H NMR (400 MHz, CDCl₃): δ 7.63 (d, J=8.3 Hz, 2H), 7.34 (d,J=8.3 Hz, 2H), 7.30 (s, 1H) 7.50 (m, 2H), 4.89 (d, J=13.0 Hz, 1H), 4.81(s, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 3.30 (t,J=13.0 Hz, 1H), 3.01-2.84 (m, 4H), 2.34 (s,3H), 2.06 (d, J=13.7 Hz, 1H),1.86 (d, J=12.9 Hz, 1H), 1.76 (q, J=12.8 Hz, 1H), 1.57 (q, J=11.7 Hz,1H).

Compound 2.1. 5-Iodo-2,4-dimethylbenzoic acid. A solution of2,4-dimethylbenzoic acid (20 g, 133.18 mmol, 1.00 equiv), sodiumperiodate (14.27 g, 66.72 mmol, 0.50 equiv), iodine (37.25 g, 146.76mmol, 1.10 equiv), and sulfuric acid (1.96 g, 19.98 mmol, 0.15 equiv) inacetic acid (150 mL) was stirred at 110° C. in an oil bath. After 6 h,the reaction mixture was allowed to reach ambient temperature and wasthen diluted with 1.2 L of water. To this was carefully added 800 mL ofaq Na₂S₂O₃ (aq., sat.). The resulting solids were collected byfiltration, dissolved in 1.2 L of ethyl acetate, and washed with 1×300mL of Na₂S₂O₃ (aq., sat.) followed by 1×400 mL of brine. The organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude residue was re-crystallized from ethanol:H₂O (2:1) to yield 30 g(82%) of the title compound as a white solid.

Compound 2.2. Methyl 5-iodo-2,4-dimethylbenzoate. A solution of5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 10 g, 32.60 mmol, 1.00equiv, 90%) and sulfuric acid (10 mL) in methanol (100 mL) was stirredovernight at 80° C. After cooling to room temperature, the mixture wasconcentrated under reduced pressure and the residue was diluted with 200mL of ethyl acetate. The resulting mixture was washed with 3×50 mL ofwater, 2×50 mL of sodium bicarbonate (aq. sat.), followed by 2×50 mL ofbrine. The organic phase was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 9.2 g (88%) of the titlecompound as a yellow oil.

Compound 2.3. Methyl 5-cyano-2,4-dimethylbenzoate. A solution of methyl5-iodo-2,4-dimethylbenzoate (compound 2.2, 9.2 g, 31.71 mmol, 1.00equiv), Zn(CN)₂ (4.46 g, 38.12 mmol, 1.20 equiv), and Pd(PPh₃)₄ (2.93 g,2.54 mmol, 0.08 equiv) in N,N-dimethylformamide (120 mL) was stirredunder a nitrogen atmosphere at 100° C. overnight. After cooling to roomtemperature, the reaction was then quenched by careful addition of 100mL of FeSO₄ (aq., sat.) and diluted with ethyl acetate. The resultingmixture was stirred vigorously then filtered through celite and washedwith 1 M FeSO₄, water, and ethyl acetate. The layers were separated andthe aqueous phase was extracted with 2×100 mL of ethyl acetate. Thecombined organic layers were washed with 2×20 mL of brine, dried(Na₂SO₄), and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:5) as eluent to yield 6.2 g (93%) of thetitle compound as a white solid.

Compound 2.4. Methyl 5-(N′-hydroxycarbamimidoyl)-2,4-dimethylbenzoate. Asolution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 6 g,28.54 mmol, 1.00 equiv, 90%) and NH₂OH (10 mL, 5.00 equiv, 50% in water)in EtOH (20 mL) was stirred at 100° C. in an oil bath. After 2 h, themixture was cooled to room temperature and concentrated under reducedpressure. The residue was diluted with 100 mL of ethyl acetate, washedwith 2×20 mL of brine, dried (Na₂SO₄), and concentrated under reducedpressure to yield 4.66 g (66%) of the title compound as a white solid.

Compound 2.5. Methyl 5-carbarmimidoyl-2,4-dimethylbenzoatehydrochloride. A solution of methyl5-(N′-hydroxycarbamimidoyl)-2,4-dimethylbenzoate (compound 2.4, 4.66 g,18.87 mmol, 1.00 equiv, 90%) and Ac₂O (2.36 g, 23.09 mmol, 1.10 equiv)in AcOH (21 mL) was stirred at room temperature. After 5 minutes, theflask was purged with nitrogen and HCOOK (8.8 g, 104.76 mmol, 5.00equiv) and palladium on carbon (10%, 2.33 g) were added. The flask waspurged with nitrogen followed by hydrogen. The mixture was stirred undera hydrogen atmosphere (balloon) at room temperature for 4 h. Afterpurging the system with nitrogen, the solids were removed by filtration,and the filtrate was concentrated under reduced pressure. The residuewas dissolved in 50 mL of ethanol and the pH was adjusted to 5-6 withhydrogen chloride (aq., 5 M). The resulting solids were removed byfiltration and the filtrate was concentrated under reduced pressure toyield 4 g of the title compound as a white solid.

Compound 2.6. tert-Butyl2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.A mixture of methyl methyl 5-carbamimidoyl-2,4-dimethylbenzoatehydrochloride (compound 2.5, 500 mg, 90%), tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (860 mg, 2.78 mmol), and potassiumcarbonate (570 mg, 4.12 mmol) in CH₃CN (15 mL) was stirred overnightunder nitrogen at 80° C. After cooling to ambient temperature, thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in 25 mL of ethyl acetate and washed with 2×10 mL of H₂O.The organic phase was dried (Na₂SO₄) and concentrated under reducedpressure. The crude product thus obtained was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:3) as eluentto yield 0.3 g of the title compound as a white solid.

Compound 2.7.5-(5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid. A mixture of tert-butyl2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 2.6, 300 mg, 0.70 mmol, 1.00 equiv, 90%) and sodium hydroxide(62 mg, 1.55 mmol, 2.00 equiv) in 15 mL methanol/H₂O (2:1) was stirredfor at 40° C. in an oil bath. After 2 h, the reaction mixture wasconcentrated to about ⅓ of the volume under reduced pressure. The pHvalue of the remaining mixture was adjusted to 3-4 with hydrogenchloride (aq., 1 M). The resulting solids were collected by filtrationand dried in an oven under reduced pressure to yield 0.2 g (69%) of thetitle compound as a yellow solid.

Compound 2.8. tert-Butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.A solution of compound 2.7 (125 mg, 0.30 mmol, 1.00 equiv, 90%), DIEA(130.5 mg, 1.01 mmol, 3.00 equiv), HBTU (256.2 mg, 0.68 mmol, 2.00equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,75 mg, 0.30 mmol. 1.00 equiv) in DMF (5 mL) was stirred overnight atroom temperature. The reaction mixture was then diluted with 50 mL ofethyl acetate, washed with 2×20 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography and purified using ethylacetate/petroleum ether (1:1) to yield 0.1 g (55%) of the title compoundas a yellow solid.

Compound 2.9.4-(1-(2,4-Dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.To a solution of tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 2.8, 100 mg, 0.17 mmol, 1.00 equiv, 90%) in dichloromethane (3mL) was added trifluoroacetic acid (1 mL). The resulting mixture wasstirred at room temperature. After 2 h, the reaction mixture wasconcentrated under reduced pressure. The residue was taken up indichloromethane and washed with sodium bicarbonate (aq., sat.). Theorganic phase was dried (Na₂SO₄) and concentrated under reduced pressureto yield 0.1 g (68%) of the title compound as a yellow solid.

Compound 2.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.To a stirred mixture of4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 2.9, 20 mg, 0.02 mmol, 1.00 equiv, 50%) in DMF (2 mL) undernitrogen was added a solution of Ac₂O (2.4 mg, 0.02 mmol, 1.00 equiv) inDMF (0.2 mL) dropwise at 0° C. The resulting solution was stirred for 1h at 0˜3° C. in a water/ice bath. The reaction mixture was then dilutedwith 50 mL of ethyl acetate and washed with 2×20 mL of brine. Theorganic phase was dried (Na₂SO₄) and concentrated under reducedpressure. The crude residue (50 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-006 (Waters)): Column, xbridge C18,mobile phase, WATER, WITH 0.05% NH₃.H₂O and CH₃CN (hold 5% CH₃CN in 2min, up to 20%-46% in 10 min, up to 100% in 12 min, down to 20% in 14min); Detector, UV 254/220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 5.5 mg of the title compound as awhite solid. m/z (ES+) 482 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d,J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.39-7.28 (m, 2H), 4.90 (m, 1H,partially obscured by the solvent peak), 4.67 and 4.62 (2 singlets,acetamide rotamers, MeCONCH₂-imidazole, 2H), 3.92 (m, 2H), 3.66 (m, 1H),3.23 (m, 1H), 3.00 (m, 2H), 2.85-2.76 (m, 2H), 2.48 (s, 3H), 2.41 and2.31 (2 singlets, aryl amide rotamers, ArCH₃, 3H), 2.25 and 2.22 (2singlets, acetamide rotamers, CH₃CON, 3H), 2.04 (m, 1H), 1.92-1.20 (m,3H).

Compound 3.4-(1-(3-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 468 (M+H)⁻.

Compound 4.4-(1-(4-Methyl-3-(5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 504 (M+H)⁻.

Compound 5.4-(1-(5-(5-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 546 (M+H)⁺.

Compound 6.4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)-2-fluorobenzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2, m/z (ES+) 459 (M+H)⁻.

Compound 7.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-sulfonamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 547 (M+H)⁺.

Compound 8.(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 484 (M+H)⁺.

Compound 9.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 496 (M+H)⁺.

Compound 11.1. tert-Butyl4-(4-cyanophenyl)-4-fluoropiperidine-1-carboxylate. To a stirredsolution of compound 1.2 (5 g, 16.54 mmol, 1.00 equiv) indichloromethane (250 mL) under nitrogen at −78° C. was added dropwiseDeoxo-Fluor® (4.4 g, 19.89 mmol, 1.20 equiv). The resulting mixture wasstirred for 1 h at −78° C. The reaction mixture was then carefullyquenched by the addition of 50 mL of sodium bicarbonate (aq. sat.) andextracted with 3×100 mL of dichloromethane. The combined organic layerswere washed with 150 mL of brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:30) as eluent to yield 2.5 g (35%) of thetitle compound as a white solid.

Compound 11.2. 4-(4-Fluoropiperidin-4-yl)benzonitrile. To a stirredsolution of compound 11.1 (620 mg, 1.02 mmol, 1.00 equiv, 50%) in DCM(40 mL) was added dropwise trifluoroacetic acid (6 g, 52.62 mmol, 51.66equiv). After stirring at ambient temperature for 2 h, the mixture wasconcentrated under reduced pressure. The residue was taken up in DCM andtreated with aqueous sodium bicarbonate. The phases were separated andthe aqueous layer was extracted with 2×50 mL DCM. The combined organiclayers were dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to yield 0.4 g of the title compound as a lightyellow solid. m/z (ES+) 205 (M+H)⁺.

Compound 11.2 HCl salt. 4-(4-Fluoropiperidin-4-yl)benzonitrilehydrochloride. The title compound was prepared using standard chemicalmanipulations and a procedure similar to that used for the preparationof compound 1.5 and using compound 11.1 in place of compound 1.4. m/z(ES+) 205 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.83 (d, J=6.3 Hz, 2H),7.68 (d, J=6.3 Hz, 2H), 3.55-3.32 (m, 4H), 2.58-2.40 (m, 2H), 2.28-2.22(m, 2H).

Compound 11.4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compoundwas prepared using standard chemical manipulations and proceduressimilar to those used for the preparation of compounds 1 and 2 and usingcompound 11.2 in place of compound 1.5. m/z (ES+) 459 (M+H)⁺.

Compound 12.(4-(4-Chlorophenyl)piperidin-1-yl)(2,4-dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 450 (M+H)⁻.

Compound 13.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carboxamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 482 (M+H)⁺.

Compound 14.4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 441 (M+H)⁺.

Compound 15.(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(4-(trifluoromethoxy)phenyl)piperidin4-yl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 500 (M+H)⁺.

Compound 16.1.N²-(2-Methoxyethyl)-N²-methyl-5-nitropyridine-2,4-diamine. A solution of2-chloro-5-nitropyridin-4-amine (500 mg, 2.88 mmol, 1.00 equiv),triethylamine (1.167 g, 11.53 mmol. 4.00 equiv), and(2-methoxyethyl)(methyl)amine (514 mg, 5.77 mmol, 2.00 equiv) in DMF (20mL) was stirred in a sealed tube at 55° C. behind a blast shieldovernight. After cooling to room temperature, the mixture was dilutedwith 100 mL of water and extracted with 3×150 mL of ethyl acetate. Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield 723 mg (crude) of the title compound as a darkred oil.

Compound 16.2. N²-(2-Methoxyethyl)-N²-methylpyridine-2,4,5-triamine.Around-bottom flask, containing a solution of compound 16.1 (400 mg,1.77 mmol, 1.00 equiv)) in methanol (30 mL) was purged with nitrogengas. To the solution was then added palladium on carbon (40 mg, 10%, 60%water). The flask was purged further with nitrogen and the atmospherewas then changed to hydrogen. The mixture was stirred at roomtemperature under a balloon with hydrogen for 4 h. After purging thesystem with nitrogen, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to yield 300 mg (86%)of the title compound as a light brown solid. The crude product wasfound to be unstable and used immediately.

Compound 16.3. 5-Formyl-2,4-dimethylbenzoic acid. To a stirred solutionof 5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 5 g, 18.11 mmol, 1.00equiv) in tetrahydrofuran (150 mL) under nitrogen at −78° C. was addedn-BuLi (2.5 M in THF, 18 mL, 2.50 equiv) dropwise. After stirring at−78° C. for 1 h, DMF (5 g, 68.4 mmol, 3.80 equiv) was added dropwise.The resulting mixture was stirred at −78° C. for an additional 0.5 h andthen carefully quenched by slow addition of 50 mL of water. The pH wasthen adjusted to ˜3-4 using aqueous HCl (aq., 6 M). The mixture wasextracted with 3×200 mL of ethyl acetate. The combined organic layerswere dried (Na₂SO₄) and concentrated under reduced pressure. The residuethus obtained was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:10-1:5) as gradient to yield 2.4 g(74%) of the title compound as a white solid.

Compound 16.4.4-(1-(5-Formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. To astirred solution of 5-formyl-2,4-dimethylbenzoic acid (compound 16.3,950 mg, 5.33 mmol, 1.10 equiv) in DMF (1:5 mL) was added DIEA (2.48 g,19.19 mmol, 4.00 equiv) followed by HBTU (3.67 g, 9.68 mmol, 2.00equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,1.07 g, 4.80 mmol, 1.00 equiv). After stirring overnight at ambienttemperature, the reaction was quenched by the addition of 60 mL ofwater. The resulting mixture was extracted with 3×150 mL of ethylacetate and the organic layers were combined, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:10-1:3) as eluent to yield 1.4 g (84%) of thetitle compound as a brown oil.

Compound 16,4-(1-(5-(6-((2-Methoxyethyl)(methyl)amino)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.A solution of compound 16.2 (300 mg, 1.53 mmol, 1.30 equiv), compound16.4 (407 mg, 1.17 mmol, 1.00 equiv), and ammonium acetate (362 mg, 4.70mmol, 4.00 equiv) in ethanol (20 mL) was stirred overnight at 70° C. inan oil bath. The resulting mixture was then concentrated under vacuumand the residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:10-2:1) as eluent to yield 200 mg ofproduct which was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006 (Waters)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH₃CN (hold 5.0% CH3CNin 2 min, up to 25.0% in 1 min, up to 55.0% in 12 min, up to 100.0% in 1min); Detector, UV 254/220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 150 mg (24%) of the titlecompound as a white solid. m/z (ES+) 523 (M+H)⁺. ¹H NMR (300 MHz,CDCl₃): δ 8.57-8.38 (m, 1H), 7.78-7.53 (m, 4H), 7.34 (d, J=7.5 Hz, 2H),7.28-7.12 (m, 2H), 5.06-4.88 (m, 1H), 3.71 (app s, 5H), 3.50 (s, 3H),3.41-3.05 (m, 4H), 3.01-2.75 (m, 2H), 2.68 (s, 3H), 2.42 & 2.31 (2singlets, amide rotamers, ArCH₃, 3H), 2.12-1.93 (m, 1H), 1.93-1.39 (m,3H).

Compound 17.4-(1-(2,4-Dimethyl-5-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 521 (M+H)⁺.

Compound 18.4-(1-(2,4-Dimethyl-5-(6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 534 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆): 8.73 (s, 1H), 7.76 (d,J=7.5 Hz, 2H), 7.66 & 7.56 (2 singlets, amide rotamers, Ar—H, 1H), 7.49(d, J=8.1 Hz, 2H), 7.37 (s, 1H), 7.12 (s, 1H), 4.81-4.67 (m, 1H), 4.30(br s, 2H), 3.70-3.37 (m, 3H), 3.37-3.05 (m, 5H), 3.05-1.80 (m, 5H),2.60 (s, 3H), 2.37 & 2.27 (2 singlets, amide rotamers, Ar—CH₃, 3H),2.02-1.87 (m, 1H), 1.87-2.40 (m, 3H).

Compound 19.4-(1-(2,4-Dimethyl-5-(6-(piperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 519 (M+H)⁻.

Compound 20.1. 5-Nitro-2-(pyrrolidin-1-yl)pyridin-4-amine. A 500 mLround bottom flask equipped with a reflux condenser was charged with2-chloro-5-nitropyridin-4-amine (2.00 g, 11.5 mmol, 1.0 equiv),pyrrolidine (2.86 mL, 34.6 mmol, 3.0 equiv), potassium carbonate (4.78g, 34.6 mmol, 3.0 equiv) and acetonitrile (50 mL). The mixture washeated at 70° C. overnight under nitrogen then cooled to roomtemperature. The yellow solids were collected by filtration and washedwith acetonitrile, water and hexanes. The solids were dried to obtainthe title compound as a bright yellow solid (1.43 g, 1^(st) crop). Thesolvents from the filtrate were removed and the aqueous was extractedwith ethyl acetate. The organic extracts was dried (Na₂SO₄), filteredand removed in vacuo to obtain additional product as an orange/yellowsolid (820 mg, 2^(nd) crop). The 2^(nd) crop of product was trituratedwith ethyl acetate (3 mL) and then filtered and washed with ethylacetate (2×1 mL) and diethyl ether (3 mL) to obtain a bright yellowsolid (751 mg). The total yield of5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine obtained was 2.18 g (91%).m/z (ES+) 209.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 7.39s, 2H), 5.63 (s, 1H), 3.40 (br s, 4H), 1.93 (br s, 4H).

Compound 20.2. 6-(Pyrrolidin-1-yl)pyridine-3,4-diamine. To a 100 mLround bottom flask was added 5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine(compound 20.1, 800 mg, 3.84 mmol, 1.0 equiv) and Pd on carbon (10 wt %Pd, 400 mg, 0.38 mmol, 0.1 equiv). The system was purged with nitrogenand charged with methanol (19 mL) followed by hydrogen. The mixture wasstirred at room temperature under hydrogen for 4 hours then purged withnitrogen. The mixture was filtered though celite and washed extensivelywith MeOH. The solvents were removed in vacuo to obtain the titlecompound as a purple solid (641 mg, 94%). m/z (ES+) 179.3 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆): δ 7.27 (s, 1H), 5.62 (s, 1H), 5.14 (br s, 2H), 3.67(br s, 2H), 3.23-3.13 (m, 4H), 1.91-1.79 (m, 4H).

Compound 20.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4yl)benzonitrile. To a 100 mL round bottom flask was added6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 20.2, 641 mg, 3.60mmol, 1.0 equiv),4-(1-(5-formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound16.4, 1.25 g, 3.60 mmol, 1.0 equiv), sodium metabisulfite (890 mg, 4.68mmol, 1.3 equiv) and DMF (36 mL). The mixture was heated at 100° C.under air for 22 hours then allowed to cool to room temperature. Water(80 mL) was added slowly to the stirred solution until no furtherproduct precipitated. The solids were filtered and washed with water(2×15 mL) and dried to a brown solid (1.42 g). Additional productprecipitated from the filtrate upon standing which was filtered andwashed with water (2×10 mL) to obtain an off white solid (241 mg). Theabove reaction was repeated a second time in the exact manner andquantities as described to yield additional product (1.26 g of brownsolid upon initial precipitation, plus 288 mg of off white solid fromadditional precipitation). The aqueous filtrates from the two reactionswere combined and aqueous NaHCO₃ was added to adjust the pH to 7. Theaqueous was extracted with DCM/12% MeOH (300 mL), dried (Na₂SO₄),filtered and evaporated to obtain a brown solid (547 mg). All productsobtained were combined and purified by silica gel chromatography(DCM/MeOH) to obtain the title compound as a yellow solid (2.37 g, 65%based on the theoretical yield for the two reactions). m/z (ES+) 505.1(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 12.41 (br s, 1H), 8.52 (s, 1H),7.77 (d, J=8.2 Hz, 2H), 7.66 & 7.56 (2 br singlets, amide rotamers, ArH,1H), 7.49 (s, J=8.2 Hz, 2H), 7.29 (s, 1H), 6.31 (br s, 1H), 4.79-4.67(m, 1H), 3.54-3.34 (m, 5H), 3.17 (app t, J=11.8, 1H), 2.99-2.82 (m, 2H),2.63 (s, 3H), 2.33 & 2.24 (2 singlets, amide rotamers, ArCH₃, 3H),2.03-1.87 (m, 5H), 1.82-1.38 (m, 3H). Elemental analysis (C₃₁H₃₂N₆O.1.3H₂O, 528.04), found (calcd), C: 70.66 (70.51); H: 6.54 (6.60); N: 15.78(15.92).

Compound 20 HCl salt.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrilehydrochloride. Dichloromethane (˜50 mL) was added to4-(1-(2,4-dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 20 free base, 2.31 g, 4.58 mmol) until it completely dissolvedand then 4M HCl in dioxane (5 mL, 20 mmol, 4.3 equiv) was added. Thesolvents were removed and the residue was dissolved in DCM and removedin vacuo. The resulting hydrochloride salt was recrystallized fromboiling ethanol (180 mL) and allowed to cool to room temperature slowly.The mixture sat at room temperature overnight and then placed in thefreezer for 4 hours. The resulting solids were filtered and washed withcold ethanol (25 mL) followed by diethyl ether (25 mL). The solids weredried to obtain an off white to light grey solid (1.82 g, 73%). ¹H NMR(400 MHz, DMSO-d₆): δ 13.59 & 13.46 (2 br singlets, imidazole NHtautomers, 1H), 13.29 (br s, 1H), 8.62 (br s, 1H), 7.83 & 7.67 (2singlets, amide rotamers, ArH, 1H,), 7.78 (d, J=7.8 Hz, 2H), 7.58-7.45(m, 2H), 7.37 (s, 1H), 6.71 (br s, 1H), 4.80-4.68 (m, 1H), 3.65-3.38 (m,5H), 3.25-3.12 (m, 1H), 3.00-2.82 (m, 2H), 2.66 (s, 3H), 2.37 & 2.27 (2singlets, amide rotamers, ArCH₃, 3H), 2.13-2.01 (m, 4H), 1.98-1.87 (m,1H), 1.82-1.40 (m, 3H). Elemental analysis (C₃₁H₃₂N6O.1.0 HCl.2.4 H₂O,584.32), found (calcd), C: 63.80 (63.72); H: 6.32 (6.52); N: 14.25(14.38).

Compound 20 MsOH salt.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrilemethanesulfonate.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrilehydrochloride (compound 20 HCl salt, 1.82 g, 3.36 mmol) was added towater (100 mL) plus saturated NaHCO₃ (50 mL) and extracted with 1:1DCM/EtOAc (500 mL) plus MeOH (25 mL). Once the entire product completelydissolved, the layers were separated and the aqueous was extracted withadditional 1:1 DCM/EtOAc (100 mL). The combined organics was dried(Na₂SO₄), filtered and evaporated to a light yellow powder (1.68 g, 3.33mmol). The free base material was dissolved in hot acetonitrile (10 mL),then a 1.0 M aqueous methanesulfonic acid solution (3.33 mL, 3.33 mmol,1.0 equiv) was added and mixed well. Additional water (6 mL) was addedand the mixture was frozen and dried on the lyophilizer to obtain ayellow powder (1.99 g, 99%). m/z (ES+) 505.1 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 13.29 (br s, 1H), 13.10 (br s, 1H), 8.65 (br s, 1H), 7.78(d, J=8.2 Hz, 2H), 7.74 & 7.64 (2 singlets, amide rotamers, ArH, 1H,),7.50 (d, J=8.3 Hz, 2H), 7.37 (s, 1H), 6.74 (br s, 1H), 4.80-4.68 (m,1H), 3.65-3.38 (m, 5H), 3.26-3.12 (m, 1H), 3.01-2.83 (m, 2H), 2.64 (s,3H), 2.37 & 2.27 (2 singlets, amide rotamers, ArCH₃, 3H), 2.32 (s, 3H)2.12-2.00 (m, 4H), 1.98-1.88 (m, 1H), 1.82-1.39 (m, 3H). Elementalanalysis (C₃₁H₃₂N₆O.1.0 MsOH.1.7 H₂O, 631.36), found (calcd), C: 60.96(60.88); H: 6.14 (6.29); N: 13.21 (13.31); S: 5.08 (5.08).

Compound 21.4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 491 (M+H)⁺.

Compound 22.4-(1-(2,4-Dimethyl-5-(6-(methylsulfonyl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrite.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 514 (M+H)⁺.

Compound 23.4-(1-(2,4-Dimethyl-5-(6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 514 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆+D₂O): δ 8.87 (d, J=1.8 Hz,1H), 8.52 (d, J=2.1 Hz, 1H), 7.74 (d, J=7.5 Hz, 2H), 7.66 & 7.56 (2singlets, amide rotamers, Ar—H, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.38 (br s,1H), 4.76-4.63 (m, 1H), 3.57-3.38 (m, 1H), 3.31 (s, 3H), 3.28-3.13 (m,1H), 3.03-2.85 (m, 2H), 2.60 (s, 3H), 2.35 & 2.27 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.00-1.85 (m, 1H), 1.85-1.32 (m, 3H).

Compound 24.4-(1-(5-(5-(Azetidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing 6-chloro-3-nitropyridin-2-amine and azetidine hydrochloride inplace of 2-chloro-5-nitropyridin-4-amine and(2-methoxyethyl)(methyl)amine respectively. m/z (ES+) 491 (M+H)⁺. ¹H NMR(300 MHz, CD₃OD): δ 8.06 (d, J=9.0 Hz, 1H), 7.70-7.42 (m, 6H), 6.60 (d,J=9.0 Hz, 1H), 4.90 (m, 1H, partially obscured by the solvent peak),4.32 (m, 4H), 3.65 (m, 1H), 3.03 (m, 1H), 2.62 (s, 3H), 2.57 (m, 3H),2.48 and 2.38 (2 singlets, amide rotamers, ArCH₃, 3H), 2.04 (m, 1H),1.96-1.68 (m, 4H).

Compound 25.4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 andusing compound 11.2 in place of compound 1.5. m/z (ES+) 509 (M+H)⁺.

Compound 26.1. tert-Butyl4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate. To a stirredsolution of 2,5-dibromopyridine (10 g, 42.19 mmol, 1.00 equiv) intoluene (1000 mL) under nitrogen at −78° C. was added dropwise n-BuLi(18 mL, 2.5 M in toluene). After 1 h at −78° C., a solution oftert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.25 mmol, 1.19 equiv)in toluene (200 mL) was added dropwise while stirring. After anadditional 2 h of stirring at −78° C., the reaction was then carefullyquenched by the addition of 300 mL of water. The resulting mixture wasextracted with 3×500 mL of ethyl acetate. The combined organic layerswere washed with 1×300 mL of brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:100-1:5) to yield 6.5 g (42%) of the title compound as a yellow oil.

Compound 26.2. tert-Butyl4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate. A mixture oftert-butyl 4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate(compound 26.1, 1 g, 2.80 mmol, 1.00 equiv), zinc cyanide (400 mg, 3.42mmol, 1.22 equiv), Pd(PPh₃)₄ (200 mg, 0.17 mmol, 0.06 equiv) in DMF (50mL) was stirred under nitrogen for 2 h at 100° C. After cooling to roomtemperature, the reaction was then quenched by careful addition of 300mL of FeSO₄ (aq., sat.) and diluted with ethyl acetate. The resultingmixture was stirred vigorously then filtered through celite and washedwith 1 M FeSO₄, water, and ethyl acetate. The layers were separated andthe aqueous phase was extracted with 2×100 mL of ethyl acetate. Thecombined organic layers were washed with 1×100 mL of brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:100-1:4) yield 0.5 g (58%) of the titlecompound as a yellow oil.

Compound 26.3. tert-Butyl4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate. To a solutionof tert-butyl 4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate(compound 26.2, 1 g, 3.13 mmol, 1.00 equiv, 95%) in dichloromethane (50mL) under nitrogen at −78° C. was added dropwise a solution ofbis(2-methoxyethyl)aminosulfur trifluoride (830 mg, 3.75 mmol, 1.20equiv) in dichloromethane (10 mL) during the course of 1 min. Theresulting mixture was stirred for 1 h at −78° C. The reaction was thencarefully quenched by dropwise addition of water and washed with 2×20 mLof sodium bicarbonate(aq) followed by 3×20 mL of brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:10) to yield 0.38 g(38%) of the title compound as a white solid.

Compound 26.4. 6-(4-Fluoropiperidin-4-yl)nicotinonitriletrifluoroacetate. To a stirred solution of tert-butyl4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate (compound 26.3,1 g, 3.11 mmol, 1.00 equiv, 95%) in dichloromethane (20 mL) was addeddropwise TFA (3.75 g, 32.89 mmol, 10.57 equiv). After stirring for 1 hat 25° C., the mixture was concentrated under reduced pressure to yield0.5 g of the title compound as a brown oil.

Compound 26.6-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)nicotinonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing compound 26.4 in place of compound 1.5. m/z (ES+) 509 (M+H)⁺.

Compound 27.4-(1-(4-Methyl-3-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing 3-bromo-4-methylbenzoic acid in place of5-iodo-2,4-dimethythenzoic acid. m/z (ES+) 491 (M+H)⁺.

Compound 28.4-(1-(3-(1H-Imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compounds 16 and27. m/z (ES+) 422 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 9.35 (s, 1H), 8.60(d, J=6.6 Hz, 1H), 8.19 (d, J=6.6 Hz, 1H), 7.92 (s, 1H), 7.73-7.58 (m,4H), 7.50 (d, J=8.1 Hz, 1H), ˜4.9 (1H, partially obscured by waterpeak), 4.06-3.87 (m, 1H), 3.13-2.95 (m, 3H), 2.73 (s, 3H), 2.11-1.63 (m,4H).

Compound 29.4-(1-(3-(1H-Benzo[d]imidazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compounds 16 and27. m/z (ES+) 421 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.87-7.77 (m, 3H),7.75-7.60 (m, 4H), 7.60-7.47 (m, 4H), ˜4.85 (1H, partially obscured bywater peak), 4.04-3.89 (m, 1H), 3.13-2.95 (m, 3H), 2.61 (s, 3H),2.11-1.69 (m, 4H).

Compound 30.4-(1-(3-(6-Chloro-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compounds 16 and27. m/z (ES+) 456 (M+H)⁺.

Compound 31.4-(1-(2-Methyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing 5-bromo-2-methylbenzoic acid in place of5-iodo-2,4-dimethylbenzoic acid (compound 2.1). m/z (ES+) 491 (M+H)⁺. ¹HNMR (300 MHz, DMSO-d₆): δ 12.63 (br s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.01& 7.91 (2 singlets, amide rotamers, Ar—H, 1H), 7.81 (d, J=6.6 Hz, 2H),7.58-7.42 (m, 3H), 6.31 (s, 1H), 4.85 (m, 1H), 3.57-3.35 (m, 5H),3.30-3.13 (m, 1H), 3.07-1.85 (m, 2H), 2.39 & 2.29 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.10-1.89 (m, 5H), 1.87-1.40 (m, 3H).

Compound 32.4-(1-(2-Methoxy-5-(6-(pyrroidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 507 (M+H)⁺.

Compound 33.2-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 502 (M+H)⁺.

Compound 34.4-(1-(2-Chloro-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 511 (M+H)⁺.

Compound 35.4-(1-(5-(6-(Pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2-(trifluoromethoxy)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 561 (M+H)⁺.

Compound 36.4-(1-(3-(6-(Pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 477 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 8.44 (s, 1H), 8.25-8.17 (m,2H), 7.77-7.63 (m, 4H), 7.51 (d, J=8.1 Hz, 2H), 6.59 (s, 1H), ˜4.85 (1H,partially obscured by water peak), 3.98-3.83 (m, 1H), 3.61-3.48 (m, 4H),˜3.4 (1H, partially obscured by methanol solvent peak), 3.12-2.96 (m,2H), 2.22-2.09 (m, 4H), 2.09-1.95 (m, 1H), 1.95 (m, 3H).

Compound 37.4-(1-(3-(6-(Isopropylamino)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 465 (M+H)⁺.

Compound 38.1. Methyl tetrahydrofuran-3-carboxylate. A solution oftetrahydrofuran-3-carboxylic acid (540 mg, 4.65 mmol, 1.00 equiv) andTsOH (10 mg, 0.06 mmol, 0.01 equiv) in methanol (40 mL) was stirred at66° C. in an oil bath. After 16 h, the resulting mixture was cooled toroom temperature and concentrated under reduced pressure. The residuewas dissolved in 10 mL of ether, washed with 1×20 mL of NaHCO₃ (aq.,sat.) followed by 3×20 mL of brine, and concentrated under reducedpressure to yield 0.40 g (66%) of the title compound as a colorless oil.

Compound 38.2. Tetrahydrofuran-3-carbohydrazide. Into around-bottomflask, was placed hydrazine hydrate (20 mL). To this was added methyltetrahydrofuran-3-carboxylate (compound 38.1, 390 mg, 3.00 mmol, 1.00equiv) dropwise with stirring. The resulting mixture was stirred at 50°C. in an oil bath. After 3 h, the reaction mixture was concentrated anddried under reduced pressure to yield 0.29 g (74%) of the title compoundas a colorless oil.

Compound 38.3. Methyl 3-carbamothioyl-4-methylbenzoate. A solution ofmethyl 3-cyano-4-methylbenzoate (compound 1.7, 880 mg, 5.02 mmol, 1.00equiv) and O,O′-diethyl dithiophosphate (1.41 g, 8.29 mmol, 1.50 equiv)in THF/H₂O (40 mL) was stirred at 80° C. (CAUTION: significant gasevolution occurs—this and all other reactions described herein should becarried out in well ventilated fume hoods). After 3 h, the organicsolvent was removed under reduced pressure and the residual aqueousphase was extracted with 3×20 mL of ethyl acetate. The combined organiclayers were concentrated under reduced pressure to yield 0.85 g (79%) ofthe title compound as a light yellow solid.

Compound 38.4. Methyl 3-(imino(methylthio)methyl)-4-methylbenzoate. To astirred solution of methyl 3-carbamothioyl-4-methylbenzoate (compound38.3, 2.10 g, 9.85 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) wasadded iodomethane (2.8 g, 19.73 mmol, 2.00 equiv) dropwise. Theresulting mixture was stirred at room temperature. After 3 h, thereaction mixture was concentrated under reduced pressure and the residuewas dried under vacuum to yield 1.6 g (73%) of the title compound as alight yellow solid.

Compound 38.5. Methyl4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoate. Asolution of tetrahydrofuran-3-carbohydrazide (compound 38.2, 195 mg,1.50 mmol, 1.50 equiv) and compound 38.4 (223 mg, 1.00 mmol, 1.00 equiv)in AcOH (30 mL) was stirred at 80° C. After 4 h, the reaction mixturewas concentrated under reduced pressure and the residue was dried underhigh-vaccum to yield 153 mg (53%) of the title compound as yellow oil.

Compound 38.6.4-Methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoic acid.To a stirred solution of compound 38.5 (57 mg, 0.20 mmol, 1.00 equiv) inmethanol (20 mL) was added sodium hydroxide (aqueous, 1 M, 0.2 mL)dropwise. The resulting mixture was stirred at room temperature. After 4h, the organic solvent was removed under reduced pressure. The residualaqueous layer was washed with 2×20 mL of ethyl acetate. The pH of theaqueous phase was then adjusted to 4 with hydrogen chloride (aq., 1 M)and the resulting solids were collected by filtration and dried to yield23 mg (42%) of the title compound as a light yellow solid.

Compound 38.4-(1-(4-Methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.A mixture of compound 38.6 (137 mg, 0.50 mmol, 1.00 equiv), HBTU (228mg, 0.60 mmol, 1.20 equiv), DIEA (162 mg, 1.25 mmol, 2.50 equiv), and4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 111 mg, 0.50 mmol,1.00 equiv) in DMF (20 mL) was stirred at room temperature. After 1 h,the reaction was quenched by the addition of 20 mL of water andresulting mixture was extracted with 3×20 mL of ethyl acetate. Thecombined organic phases were dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:100-1:3) to yield35 mg (16%) of the title compound as a brown solid. m/z (ES+) 442(M+H)⁺.

Compound 39.1. 3-Formyl-4-methylbenzoic acid. To a stirred solution of3-bromo-4-methylbenzoic acid (2.14 g, 10.00 mmol, 1.00 equiv) intetrahydrofuran (30 mL) under nitrogen at −78° C. was added n-BuLi (10mL, 2.5 M in THF, 2.50 equiv) dropwise. After stirring for 1 h below−70° C., DMF (5 mL) was slowly added. The resulting solution was warmedslowly to room temperature and stirred for 1 h. After carefullyquenching the reaction by slowly adding 50 mL of water, the pH wasadjusted to 3-4 using aqueous HCl (6 M). The resulting mixture wasextracted with 2×50 mL of ethyl acetate and the combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to yield 1.6 g (98%) of the title compound as a yellow solid.

Compound 39.2.4-(1-(3-Formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A mixture of3-formyl-4-methylbenzoic acid (compound 39.1, 660 mg, 4.02 mmol, 1.00equiv), HBTU (2 g, 5.28 mmol, 1.30 equiv) in N,N-dimethylformamide (20mL) was stirred at room temperature. After 1 h,4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 890 mg, 4.01 mmol,1.00 equiv) and DIEA (1.03 g, 7.98 mmol, 2.00 equiv) were added. Theresulting mixture was stirred for 5 h at room temperature and thenovernight at 60° C. in. After cooling to ambient temperature, thereaction mixture was diluted with 100 mL of EtOAc and washed with 2×50mL of NH₄Cl (aq., sat.) followed by 2×50 mL of sodium bicarbonate (aq.,sat). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 1 g (75%) of the titlecompound as a brown oil.

Compound 39.3.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic acid. To astirred mixture of4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound39.2, 600 mg, 1.81 mmol, 1.00 equiv) in THF (5 mL) was added dropwise asolution of KMnO₄ (1 g) in water (10 mL). The resulting mixture wasstirred overnight at 60° C. in an oil bath. After cooling to ambienttemperature, the solids were removed by filtration and the pH of thefiltrate was adjusted to ≥10 with sodium hydroxide (aqueous, 1 M). Theresulting mixture was washed with 20 mL of ethyl acetate. Aqueous 1 MHCl was then employed to adjust the pH of the aqueous layer to ˜4. Theresulting aqueous phase was extracted with 2×100 mL of ethyl acetate andthe combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 500 mg (80%) of the titlecompound as light yellow oil.

Compound 394. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoate. To astirred mixture of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic acid(compound 39.3, 1.392 g. 4.00 mmol, 1.00 equiv) in methanol (50 mL) wasadded sulfuric acid (784 mg, 7.99 mmol, 2.00 equiv), dropwise. Theresulting mixture was heated to reflux overnight in an oil bath. Aftercooling to ambient temperature, the organic solvent was removed underreduced pressure. The residue was diluted with 20 mL of EtOAc and waswashed with 1×100 mL of saturated sodium bicarbonate(aq) followed by1×100 mL of brine. The organic layer was dried (Na₂SO₄) and concentratedunder reduced pressure to yield 1.303 g (90%) of the title compound as awhite solid.

Compound 39.5.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylbenzohydrazide. Asolution of compound 39.4 (1.503 g, 4.15 mmol, 1.00 equiv) and hydrazinehydrate (10 mL) in ethanol (50 mL) was heated at reflux in an oil bath.After 2 h, the mixture was concentrated under reduced pressure and theresidue was dissolved in 20 mL of EtOAc. The resulting mixture waswashed with 1×50 mL of H₂O and 1×50 mL of brine. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure to yield 1.353 g(90%) of the title compound as a white solid

Compound 39.6.4-(1-(3-(5-Amino-1,3,4-oxadiazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.A mixture of compound 39.5 (380 mg, 1.05 mmol, 1.00 equiv) and sodiumbicarbonate (105.8 mg, 1.26 mmol, 1.20 equiv) in dioxane/H₂O (1:1) (50mL) was stirred at room temperature. After 5 minutes, cyanogen bromide(212 mg, 2.00 mmol, 2.00 equiv) was added. The resulting mixture wasstirred for 3 h at room temperature. The resulting solution was stirredfor 3 h at room temperature, then quenched with 30 mL of FeSO₄ (aq.,sat.) and diluted with ethyl acetate. The resulting mixture was stirredvigorously then filtered through celite and washed with 1 M FeSO₄,water, and ethyl acetate. The layers were separated and the aqueousphase was extracted with 2×50 mL of ethyl acetate. The combined organiclayers were washed with 2×50 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. This resulted in 397 mg (98%) of anoff-white solid.

Compound 39.4-(1-(3-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.A mixture of compound 39.6 (397 mg, 1.02 mmol, 1.00 equiv) and potassiumhydroxide (287 mg, 5.12 mmol, 5.00 equiv) in ethanol (25 mL) was heatedat reflux overnight. After cooling the reaction mixture to roomtemperature with a water bath, the pH was adjusted to with acetic acid.The resulting mixture was concentrated under reduced pressure. Theresidue was taken up in ethyl acetate and washed with water. The organiclayer was dried (Na₂SO₄) and concentrated. The crude residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:5-1:0). The product was further purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-006 (Waters)):Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH0.05% TFA and CH₃CN (hold 5.0% CH₃CN in 2 min, up to 30.0% in 1 min, upto 59.0% in 12 min, up to 100.0% in 2 min); Detector, UV 254/220 nm. Thefractions containing pure compound were combined and lyophilized toyield 51.9 mg (12%) of the title compound as a white solid. m/z (ES+)416 (M+H)⁺.

Compound 40.1. tert-Butyl4-(4-cyanophenyl)-4-hydroxyazepane-1-carboxylate. A solution of4-iodobenzonitrile (510 mg, 2.22 mmol, 1.1 equiv) in THF (3mL) was addedto a 10 mL round-bottom flask and the system purged with nitrogen. Themixture was cooled to −40° C. then isopropylmagnesium chloride (1.16 mLof a 2.0 M soln in THF, 2.32 mmol, 1.15 equiv) added dropwise over 20minutes. The resulting mixture was stirred at −40° C. for 2 hours thentert-butyl 4-oxoazepane-1-carboxylate (431 mg, 2.02 mmol, 1.0 equiv) inTHF (0.5 mL) was added dropwise over 15 minutes. The resulting mixturewas stirred at −40° C. for 1 hour then diluted into ethyl acetate (15mL) and washed with 0.2 M HCl (10 mL), 0.1 M HCl (5 mL), saturatedsodium bicarbonate (5 mL) then brine (5 mL). The organics were dried(Na₂SO₄), filtered and evaporated. To remove remaining ketone and aldolby-product, the residue was dissolved in acetonitrile (3 mL) thenhydrazine (0.2 mL) was added and heated at 60° C. for 4 hours. Themixture was diluted with EtOAc (20 mL) and washed with water (20 mL),followed by 0.5 M phosphoric acid (3×20 mL), saturated sodiumbicarbonate (10 mL) and brine (10 mL). The organics were dried (Na₂SO₄),filtered and evaporated. The residue was purified by silica columnchromatography (hexanes/ethyl acetate) to obtain the title compound as apink oil which solidified upon standing (303 mg, 47%). m/z (ES+) 317(M+H)⁺.

Compound 40.2. tert-Butyl4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate andtert-butyl5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate. In a vialcontaining tert-butyl 4-(4-cyanophenyl)-4-hydroxyazepane-1-carboxylate(compound 40.1, 200 mg, 0.63 mmol, 1.0 equiv) was added pyridine (3 mL)and phosphorus oxychloride (438 μL, 4.7 mmol, 7.5 equiv) and the mixturewas stirred at room temperature for 45 hours. The solvents were removedin vacuo and the residue was dissolved in DCM (5 mL) and washed withwater (10 mL). The aqueous layer was extracted with DCM (5 mL) and thecombined organics were washed with saturated sodium bicarbonate (2×10mL), dried (Na₂SO₄), filtered and concentrated to obtain a mixture ofthe title compounds as a pale yellow oil (167 mg, 89%). m/z (ES+) 299(M+H)⁺.

Compound 40.3. tert-Butyl 4-(4-cyanophenyl)azepane-1-carboxylate. To a25 mL round bottom flask containing a mixture of tert-butyl4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate andtert-butyl 5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate(compound 40.2, 167 mg, 0.56 mmol) was added 10% palladium on carbon (40mg) and ethyl acetate (6 mL). The system was purged with nitrogen thencharged with hydrogen and stirred at room temperature. After purging thesystem with nitrogen, the mixture was filtered through celite and thefiltrate was concentrated. The residue was purified by preparative TLCto obtain a colorless wax (77 mg, 45%). m/z (ES+) 245 (M minust-butyl+H)⁺.

Compound 40.4. 4-(Azepan-4-yl)benzonitrile. To a vial containingtert-butyl 4-(4-cyanophenyl)azepane-1-carboxylate (compound 40.3, 77 mg,0.257 mmol, 1.0 equiv) was added DCM (500 μL) and trifluoroacetic acid(198 μL, 2.57 mmol, 10 equiv) and the mixture was stirred vented for 90min. The mixture was diluted into ethyl acetate (5 mL) and washed withsaturated sodium bicarbonate (5 mL). The aqueous was adjusted to pH10-11 and extracted with addition ethyl acetate until no productremained. The combined organics were dried (Na₂SO₄), filtered andconcentrated to obtain the title compound as a yellow oil (51 mg,theoretical). m/z (ES+) 201 (M+H)⁺.

Compound 40.5. 4-(1-(3-Amino4-methylbenzoyl)azepan-4-yl)benzonitrile. Toa 4-mL vial was added 3-amino-4-methylbenzoic acid (27 mg, 0.18 mmol,1.0 equiv), 4-(azepan-4-yl)benzonitrile (compound 40.4, 40 mg, 0.2 mmol,1.1 equiv), hydroxybenzotriazole (39 mg of 20 wt % H2O, 0.23 mmol, 1.3equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (44 mg, 0.23mmol, 1.3 equiv), DMF (1 mL) and N,N-diisopropylethylamine (93 μL, 0.54mmol, 3.0 equiv). The mixture was stirred at room temperature for 4hours then diluted into ethyl acetate (10 mL) and washed with brine (10mL). The aqueous was extracted with ethyl acetate (3 mL) and thecombined organics were washed with brine (10 mL), 1 M NaH₂PO₄ (5 mL) andbrine (10 mL). The organics were dried (Na₂SO₄), filtered andconcentrated to obtain the title compound as a brown solid (45 mg, 74%).m/z (ES +) 334 (M+H)⁺.

Compound 40.6.N-(5-(4-(4-Cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-fluoronicotinamide.To a 4-mL vial containing4-(1-(3-amino-4-methylbenzoyl)azepan-4-yl)benzonitrile (compound 40.5,44 mg, 0.13 mmol, 1.0 equiv) was added dichloromethane (1 mL) andN,N-diisopropylethylamine (35 μL, 0.20 mmol, 1.5 equiv). A solution of6-fluoronicotinoyl chloride (22 mg, 0.14 mmol, 1.05 equiv) indichloromethane (1 mL) was added dropwise over about 2 minutes. Theresulting mixture was stirred at room temperature for 19 hours thendiluted with dichloromethane (5 mL) and washed with 1 M NaH₂PO₄ (3 mL),saturated sodium bicarbonate (3 mL) and brine (3 mL). The organics weredried (Na₂SO₄), filtered and concentrated to obtain the title compoundas a brown wax (64 mg, theoretical). m/z (ES+) 457 (M+H)⁺.

Compound 40.N-(5-(4-(4-Cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide.To a vial containingN-(5-(4-(4-cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-fluoronicotinamide(compound 40.6, 61 mg, 0.13 mmol) was added dimethylsulfoxide (1 mL) andisopropylamine (1 mL). The mixture was stirred at 35° C. for 2 hoursthen at room temperature for 16 hours followed by 35° C. for anadditional 4 hours. The excess isopropyl amine was removed in vacuo andthe remaining solution was purified by preparative HPLC to yield theproduct as an off white powder (TFA salt, 39 mg, 49%). m/z (ES+) 496(M+H)⁺.

Compound 41.1. 5-Nitro-2-(pyrrolidin-1-yl)pyridine. A mixture of2-chloro-5-nitropyridine (1.58 g, 10.00 mmol, 1.00 equiv), pyrrolidine(710 mg, 10.00 mmol, 1.00 equiv) and potassium carbonate (2.76 g, 20.00mmol, 2.00 equiv) in CH₃CN (20 mL) was stirred at 60° C. in an oil bath.After 2 h, the reaction mixture was allowed to reach ambienttemperature. The solids were filtered off and the filtrate wasconcentrated under reduced pressure. The residue was triturated with1×20 mL of petroleum ether to yield 1.8 g (93%) of the title compound asa yellow solid.

Compound 41.2. 6-(Pyrrolidin-1-yl)pyridin-3-amine. Around-bottom flask,containing a solution of 5-nitro-2-(pyrrolidin-1-yl)pyridine (compound40.1, 1.93 g, 10.00 mmol, 1.00 equiv) in ethanol (30 mL) was purged withnitrogen. Palladium on carbon (0.4 g, 10%, 60% water) was added. Afterfurther purging the system with nitrogen, the atmosphere was changed tohydrogen and the resulting mixture was stirred overnight at roomtemperature. After purging the system with nitrogen, the solids werefiltered off and the filtrate was concentrated under reduced pressureand dried to yield 1.6 g (98%) of the title compound as a brown solid.

Compound 41.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methyl-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)benzamide.A mixture of compound 39.3 (528 mg, 1.52 mmol, 1.00 equiv) and HBTU (635mg, 2.28 mmol, 1.50 equiv) in DMF (30 mL) was stirred for 30 min at roomtemperature. To this was added 6-(pyrrolidin-1-yl)pyridin-3-amine(compound 41.2, 299 mg, 1.82 mmol, 1.20 equiv) and DIEA (50 mg). Theresulting mixture was stirred overnight at 60° C. in an oil bath. Aftercooling to room temperature, the reaction mixture was diluted with 50 mLof EtOAc and washed with 2×30 mL of NH₄Cl (aq., sat.) followed by 2×30mL of sodium bicarbonate (aq., sat.). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-016 (Waters)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, Water with 50 mmol NH₄HCO₃ and CH₃CN (10% CH₃CN up to 32%in 3 min, up to 51% in 20 min, up to 100% in 1 min, down to 10% in 1min); Detector, UV 220NMnm. The fractions containing pure compound werecombined and lyophilized to yield 50 mg (7%) of the title compound as asolid. m/z (ES+) 494 (M+H)⁺.

Compound 42.1, 5-Amino-2,4-dimethylbenzoic acid. A mixture of methyl5-amino-2,4-dimethylbenzoate (1.2 g, 6.70 mmol, 1.00 equiv) and sodiumhydroxide (1.5 g, 37.50 mmol, 5.60 equiv) in methanol/H₂O (20/20 mL) wasstirred overnight at 50° C. After cooling to ambient temperature, theorganic phase was removed under reduced pressure. The pH of theremaining aqueous layer was adjusted to 4-5 with hydrogen chloride (aq.,2 M). The resulting solids were collected by filtration and dried toyield 1.0 g of a yellow solid.

Compound 42.2.4-(1-(5-Amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.A mixture of 5-amino-2,4-dimethylbenzoic acid (compound 42.1, 2.264 g,13.71 mmol, 1.00 equiv), HBTU (7.803 g, 20.59 mmol, 1.50 equiv),4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 2.8 g, 13.71mmol, 1.00 equiv), and DIEA (3.541 g, 27.45 mmol, 2.00 equiv) in DMF (50mL) was stirred at room temperature. After 1 h, the mixture was dilutedwith 100 mL of EtOAc and washed with 1×100 mL of water followed by 1×100mL of brine. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure to yield 3.51 g (73%) of thetitle compound as a white solid.

Compound 42.3.6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)nicotinamide.To a mixture of compound 42.2 (3.51 g, 9.99 mmol, 1.00 equiv) andtriethylamine (2.02 g, 19.96 mmol, 2.00 equiv) in DCM (50 mL) undernitrogen at 0° C. was added dropwise a solution of6-chloropyridine-3-carbonyl chloride (1.936 g, 11.00 mmol, 1.10 equiv)in DCM (50 mL). After stirring for 1 h at 0° C., the reaction mixturewas quenched by careful addition of 50 mL of water and extracted with2×50 mL of dichloromethane. The combined organic layers were washed with2×50 mL of brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to yield 4.41 g (90%) of the title compound as ayellow solid.

Compound 42.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-(isopropylamino)nicatinamide.A mixture of compound 42.3 (392 mg, 0.80 mmol, 1.00 equiv),propan-2-amine (472 mg, 7,99 mmol, 10.00 equiv), potassium carbonate(221 mg, 1.60 mmol, 2.01 equiv), KI (66.4 mg, 0.40 mmol, 0.50 equiv) inDMSO (10 mL) was heated at 100° C. in a sealed tube behind a blastshield. After 48, the mixture was allowed to reach ambient temperatureand was then diluted with 20 mL of EtOAc. The mixture was washed with1×20 mL of water followed by 1×20 mL of brine. The organic phase wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product (˜300 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-002 (Agilent)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH₃CN (15.0%CH₃CN up to 40.0% in 6 min, up to 100.0% in 2 min, down to 15.0% in 2min); Detector, uv 220 & 254 nm. The fractions containing pure compoundwere combined and lyophilized to yield 158 mg (39%) of the titlecompound as an off-white solid. m/z (ES+) 514 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD, ppm): δ 8.49 (s, 1H), 8.32 (d, J=9.9 Hz, 1H), 7.79 (d, J=8.1 Hz,2H), 7.67 (d, J=7.5 Hz, 2H), 7.40-7.22 (m, 2H), 7.07 (d, J=9.6 Hz, 1H),4.85 (m, 1H), 4.03 (m, 1H), 3.80-3.42 (m, 2H), 3.29 (m, 1H), 2.48-2.03(m, 9H), 1.95 (m, 1H), 1.39 (d, J=6.3 Hz, 6H).

Compound 43.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-morpholinonicotinamide.A mixture of compound 42.3 (392 mg, 0.80 mmol, 1.00 equiv), morpholine(348 mg, 3.99 mmol, 5.00 equiv), and potassium carbonate (221 mg, 1.60mmol, 2.01 equiv) in DMSO (10 mL) was stirred overnight at 100° C. in asealed tube behind a blast shield. After cooling to ambient temperature,the reaction mixture was diluted with 20 mL of EtOAc and was washed with1×20 mL of water followed by 1×20 mL of brine. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product (300 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-002 (Agilent)): Column, 1#-PrepC-005(XBridge C18 19*150 186002979 170130047113 03), n; mobile phase, WATERWITH 0.05% TFA and CH₃CN (15.0% CH₃CN up to 50.0% in 10 min, up to100.0% in 1 min, hold 100.0% in 1 min, down to 15.0% in 2 min);Detector, uv 220 & 254 nm. The fractions containing pure compound werecombined and lyophilized to yield 106 mg (25%) of the title compound asa white solid. m/z (ES+) 542 (M+H)⁺.

Compound 44.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-((2-methoxyethyl)(methyl)amino)nicotinamide.The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (219 mg, 50%). m/z (ES+) 544(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 8.56 (s with fine structure, 1H),8.41 (d with fine structure, J=9.9 Hz, 1H), 7.79 (br d, J=8.1 Hz, 2H),7.67 (br d, J=6.9 Hz, 2H), 7.44-7.19 (m, 3H), 4.88-4.73 (m, 1H), 3.94(t, J=5.0 Hz, 2H), 3.73 (t, J=5.0 Hz, 2H), 3.70-3.47 (m, 2H), 3.39 (s,3H), 3.36 (s, 3H), 3.36-3.21 (m, 1H), 2.46-2.22 (m, 6H), 2.22-1.85 (m,4H).

Compound 45.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-(4-methylpiperazin-1-yl)nicotinamide.The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (180 mg, 44%). m/z (ES+) 555(M+H)⁺.

Compound 46.6-(Azetidin-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)nicotinamide.The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (180 mg, 44%). m/z (ES+) 512(M+H)⁺.

Compound 47.1.6-(1-(5-Amino-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)nicotinonitrile.The title compound was synthesized in a similar manner to that describedfor 42.2 and using compound 26.4 in place of compound 1.5 to yield abrown oil (280 mg, 89%).

Compound 47.2.6-Chloro-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)nicotinamide.The title compound was synthesized in a similar manner to that describedfor compound 42.3 to yield a brown oil (350 mg, 91%).

Compound 47.6-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)nicotinamide.The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (187 mg, 54%). m/z (ES+) 527(M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆): δ 9.88 (s, 1H), 9.06 (s, 1H), 8.59(d, J=1.8 Hz, 1H), 8.43 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 8.23 (d, J=9.3 Hz,1H), 7.81 (d, J=8.1 Hz, 1H), 7.22 (s, 1H), 7.17 (br s, 1H), 6.74 (d,J=9.0 Hz, 1H), 4.68-4.53 (m, 1H), 4.23 (t, J=7.7 Hz, 4H), 3.54-3.32 (m,2H), 3.22-3.05 (m, 1H), 2.59 (q, J=7.5 Hz, 2H), 2.50-2.38 (m, 2H),2.35-1.80 (m, 7H), 1.14 (t, 3H).

Compound 48.1. Methyl 2-ethyl-4-methylbenzoate. To a stirred mixture ofZnBr₂ (13 g, 57.72 mmol, 2.00 equiv) in THF (230 mL) under nitrogen at0° C. was added dropwise EtMgBr (19.5 mL, 3 M in THF). After 30 minutesat 0° C., the temperature was lowered to −78° C. and Pd(dppf)Cl₂ (2 g,2.73 mmol, 0.09 equiv) was added followed by dropwise addition of asolution of methyl 2-bromo-4-methylbenzoate (6.6 g, 28.81 mmol, 1.00equiv) in tetrahydrofuran (200 mL). The resulting mixture was allowed toslowly reach ambient temperature and stirred under nitrogen overnight.The reaction mixture was quenched by the careful addition of 20 mL NH₄Cl(aq., sat.) and extracted with 3×100 mL of ethyl acetate. The combinedorganic layers were washed with 1×200 mL of brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:30) as eluent to yield 3.7 g (72%) of thetitle compound as a colorless oil.

Compound 48.2. 2-Ethyl-4-methylbenzoic acid. A mixture of compound 48.1,3.7 g, 20.76 mmol, 1.00 equiv) and sodium hydroxide (4 g, 100.01 mmol,4.82 equiv) in methanol/H₂O (30/20 mL was stirred overnight at 50° C.After cooling to ambient temperature, the organic solvent was removedunder reduced pressure. The pH of the residual aqueous layer wasadjusted to 3-4 with hydrogen chloride (aq., 1 M). The resultingprecipitate was collected by filtration and dried to yield in 3.0 g(83%) of the title compound as a white solid.

Compound 48.3. 2-Ethyl-4-methyl-5-nitrobenzoic acid. To a stirredmixture of 2-ethyl-4-methylbenzoic acid (compound 48.2, 2. g, 12.18mmol, 1.00 equiv) in sulfuric acid (30 mL) at −10° C. was added dropwisea solution of nitric acid (1.6 g, 16.50 mmol, 2.08 equiv) in sulfuricacid (10 mL). After stirring for 30 min at −10° C., 200 mL of H₂O/icewas carefully added and the resulting mixture was extracted with 50 mLof ethyl acetate. The organic phase was washed with 2×50 mL of brine,dried over sodium sulfate, and concentrated under reduced pressure. Thecrude product was purified by re-crystallization from ethylacetate/petroleum ether in the ratio 1:10 to yield 1.0 g (37%) of2-ethyl-4-methyl-5-nitrobenzoic acid as a light-yellow solid.

Compound 48.4. 5-Amino-2-ethyl-4-methylbenzoic acid. The title compoundwas synthesized from 48.3 (1 g, 4.78 mmol) using a procedure similar tothat described for the preparation of 1.9 to yield the title compound asa light pink solid (900 mg, 97%).

Compound 48.5.4-(1-(5-Amino-2-ethyl-4-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.A mixture of 5-amino-2-ethyl-4-methylbenzoic acid (compound 48.4, 100mg, 0.56 mmol, 1.00 equiv), 4-(4-fluoropiperidin-4-yl) benzonitrile(compound 11.2, 140 mg, 0.69 mmol, 1.23 equiv), HBTU (320 mg, 0.84 mmol,1.51 equiv), and DIEA (150 mg, 1.16 mmol, 2.08 equiv) in DMF (20 mL) wasstirred for 48 h at room temperature. Water (30 mL) was added and theresulting mixture was extracted with 3×20 mL of ethyl acetate. Thecombined organic layers were washed with 1×50 mL of brine, dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with PE:EtOAc (1:1) toyield 130 mg (38%) of the title compound as a light yellow solid.

Compound 48.6.6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)nicotinamide.The title compound was synthesized in a similar manner to that describedfor compound 42.3 and using compound 48.5 in place of compound 42.2 toyield a light yellow solid (200 mg, 87%).

Compound 48.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)-6-(isopropylamino)nicotinamide.The title compound was synthesized in a similar manner to that describedfor compound 43 and using compound 48.6 in place of compound 42.3 toyield an off-white solid (32 mg, 30%). m/z (ES+) 528 (M+H)⁺.

Compound 49.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 500(M+H)⁺.

Compound 50.1. tert-Butyl5-cyano-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate. To astirred mixture of tert-butyl4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound26.2, 500 mg, 1.65 mmol, 1.00 equiv) in pyridine (20 mL) was addeddropwise phosphoryl trichloride (2.5 g, 16.34 mmol, 9.90 equiv) at10-15° C. The resulting solution was stirred for 18 h at 15-20° C. Thereaction was then carefully quenched by the addition of 20 mL of waterand extracted with 3×100 mL of ethyl acetate. The combined organicphases were washed with 2×50 mL of aqueous HCl (1 M) followed by 1×100mL of brine. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:100 to 1:7) as eluent to yield 0.3 g (64%) of the title compound as ayellow solid.

Compound 50.2. tert-butyl4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate. Around-bottom flask,containing a solution of compound 50.1 (300 mg, 1.05 mmol, 1.00 equiv)in ethyl acetate (20 mL), was purged with nitrogen gas. To the solutionwas then added palladium on carbon (40 mg, 10%) and the flask was purgedfurther with nitrogen gas. The atmosphere was then changed to hydrogenand the mixture was stirred for 16 h at 15-20° C. After purging thesystem with nitrogen, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to yield 0.2 g (66%) ofthe title compound as a yellow oil.

Compound 50.3. 6-(Piperidin-4-yl)nicotinonitrile hydrochloride. Througha solution of tert-butyl 4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate(compound 50.2, 200 mg, 0.70 mmol, 1.00 equiv) in ethyl acetate (20 mL)was bubbled HCl gas. The resulting mixture was stirred for 40 min at5-10° C. The resulting precipitate was collected by filtration and driedto yield 150 mg (97%) of the title compound as a white solid.

Compound 50.N-(5-(4-(5-Cyanopyridin-2-yl)piperidine-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43 but using compound50.3 in place of compound 11.2. m/z (ES+) 483 (M+H)⁺.

Compound 51.1. tert-Butyl4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate. To a solutionof 2,5-dibromopyridine (10 g, 42.55 mmol, 1.00 equiv) in tetrahydrofuran(400 mL) under nitrogen at −78° C. was added dropwise n-BuLi (19 mL, 2.4M in THF). After 1 h at −78° C., a solution of tert-butyl4-oxopiperidine-1-carboxylate (9.5 g, 47.74 mmol, 1.12 equiv) intetrahydrofuran (100 mL) was added dropwise. The resulting mixture wasstirred for an additional hour at −78° C. The reaction was then warmedto −30° C. and carefully quenched by the addition of 300 mL of water.The resulting mixture was extracted with 3×200 mL of ethyl acetate andthe combined organic layers were washed with 1×200 mL of brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:3) as eluent to yield 5 g (33%) of thetitle compound as a yellow solid.

Compound 51.2. tert-Butyl4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate. To a mixtureof tert-butyl 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate(compound 51.1, 1 g, 2.81 mmol, 1.00 equiv) in DMF (50 mL) undernitrogen at 50° C. was added Zn(CN)₂ (400 mg, 3.42 mmol, 1.22 equiv) at50° C. followed by Pd(PPh₃)₄ (200 mg, 0.17 mmol, 0.06 equiv) at 80° C.The resulting mixture was then stirred for 1 h at 120° C. After coolingto ambient temperature, the reaction was quenched by the addition of 200mL of FeSO₄ (aq., sat.) and diluted with ethyl acetate. The resultingmixture was stirred vigorously then filtered through celite and washedwith 1 M FeSO₄, water, and ethyl acetate. The layers were separated andthe aqueous phase was extracted with 2×100 mL of ethyl acetate. Thecombined organic layers were washed with 1×200 mL of brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:5-1:3) as eluent to yield 0.6 g (70%) of thetitle compound as a light yellow oil.

Compound 51.3. tert-Butyl6-cyano-5′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate. To solutionof tert-butyl 4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate(compound 51.2, 600 mg, 1.98 mmol, 1.00 equiv) in pyridine (15 mL) undernitrogen at 10-15° C. was carefully added POCl₃ (3 g, 19.74 mmol, 9.97equiv). After stirring overnight under nitrogen in a water/ice bath, themixture was concentrated and the residue was dissolved in 50 mL of ethylacetate. The organic phase was washed with 1×50 mL of hydrogen chloride(aq. 1M) followed by 1×50 mL of sodium bicarbonate (aq. sat.). Theorganic layer was then dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:10) as the eluent to yield 0.26 g (46%) of the title compound as awhite solid.

Compound 51.4. tert-Butyl4-(6-cyanopyridin-3-yl)piperidine-1-carboxylate. A round-bottom flask,containing a solution of compound 51.3 (260 mg, 0.91 mmol, 1.00 equiv)in ethyl acetate (40 mL) was purged with nitrogen gas. To the solutionwas then added palladium on carbon (0.1 g, 10%, 60% water) and the flaskwas purged further with nitrogen gas. The atmosphere was then changed tohydrogen and the mixture was stirred for 16 h at 15-20° C. After purgingthe system with nitrogen, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The crude residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:5). This resulted in 0.18 g (69%) of thetitle compound as a colorless oil.

Compound 51.5. 5-(Piperidin-4-yl)picolinonitrile hydrochloride. Into acooled (5-10° C.) solution of tert-butyl4-(6-cyanopyridin-3-yl)piperidine-1-carboxylate (51.4, 180 mg, 0.63mmol, 1.00 equiv) in ethyl acetate (30 mL) was bubbled hydrogen chloridegas. The mixture was stirred for 30 min at 5-10° C. and the resultingsolids were collected by filtration and dried to yield 0.11 g (78%) of5-(piperidin-4-yl)picolinonitrile hydrochloride as a white solid.

Compound 51.N-(5-(4-(6-Cyanopyridin-3-yl)piperidine-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43 but using compound51.5 in place of compound 11.2. m/z (ES+) 483 (M+H)⁺.

Compound 52.N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridazin-3-yl)-6-(isopropylamino)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 470(M+H)⁺.

Compound 53. 2-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)piperidine-1-carbonyl)-2-methylphenyl)pyrimidine-5-carboxamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 50. m/z (ES+) 482(M+H)⁺.

Compound 54.2-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)pyrimidine-5-carboxamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 500(M+H)⁺.

Compound 55.6-(Azetidin-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethylphenyl)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 512(M+H)⁺.

Compound 56.6-(Azetidin-1-yl)-N-(5-(4-fluoro-4-(5-methoxypyridin-2-yl)piperidine-1-carbonyl)-2-methylphenyl)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 504(M+H)⁺.

Compound 57.6-(Azetidin-1-yl)-N-(2-chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)phenyl)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 518(M+H)⁺.

Compound 58.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-6-morpholinonicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 556(M+H)⁺.

Compound 60.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-6-((2-methoxyethyl)(methyl)amino)nicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 558(M+H)⁺.

Compound 61.N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-2-morpholinopyrimidine-5-carboxamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 544(M+H)⁺.

Compound 62.N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-2-morpholinopyrimidine-5-carboxamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 558(M+H)⁺.

Compound 63.N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-6-morpholinonicotinamide.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 557(M+H)⁺.

Compound 64.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea.A mixture of4-(1-(5-amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 42.2, 150 mg, 0.43 mmol, 1.00 equiv), DIEA (560 mg, 4.33 mmol,10.15 equiv), and CO(OCCl₃)₂ (160 mg, 0.54 mmol, 1.26 equiv) in DCM (50mL) was stirred under nitrogen at room temperature. After 0.5 h,(R)-(tetrahydrofuran-2-yl)methanamine (52 mg, 0.51 mmol, 1.20 equiv) wasadded. After stirring for 2 h at room temperature, the mixture waswashed with 2×50 mL of water and 1×50 mL of brine. The organic phase wasconcentrated under reduced pressure and the residue (˜200 mg) waspurified by prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATERWITH 0.05% TFA and CH₃CN (hold 5.0% CH₃CN in 2 min, up to 35.0% in 1min, up to 65.0% in 12 min, up to 100.0% in 1 min); Detector, UV 254/220nm. The fractions containing pure compound were combined and lyophilizedto yield 110 mg (54%) of the title compound as a light yellow solid. m/z(ES+) 479 (M+H)⁺. ¹H NMR (300 MHz, DMSO, ppm): δ 7.91 (d, J=8.1 Hz, 2H),7.77-7.69 (m, 4H), 7.04 (s, 1H), 6.68 (s, 1H), 4.64 (m, 1H), 3.89-3.82(m, 2H), 3.71 (m, 1H) 3.33-3.23 (m, 3H), 3.11-3.09 (m, 2H), 2.18-2.03(m, 8H), 1.97-1.84 (m, 4H), 1.57 (m, 1H).

Compound 65.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea.The title compound was synthesized in a similar manner to that describedfor compound 64 to yield a yellow solid (111 mg, 53%). m/z (ES+) 479(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.80 (d, J=8.1 Hz, 2H), 7.78-7.50 (m,3H), 7.13 (s, 1H), 4.88-4.72 (m, 1H), 3.94-8.82 (m, 1H), 3.82-3.68 (m,2H), 3.68-3.33 (m, 3H), 3.33-3.19 (m, 2H), 2.42-2.08 (m, 8H), 2.08-1.74(m, 4H), 1.74-1.54 (m, 2H).

Compound 66.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was synthesized in a similar manner to that describedfor compound 64 to yield a light yellow solid (105 mg, 53%). m/z (ES+)465 (M+H)⁺.

Compound 67.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea.The title compound was synthesized in a similar manner to that describedfor compound 64 but using compound 48.5 in place of compound 42.2. m/z(ES+) 493 (M+H)⁺.

Compound 68.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea.The title compound was synthesized in a similar manner to that describedfor compound 64 but using compound 48.5 in place of compound 42.2. m/z(ES+) 493 (M+H)⁺.

Compound 69.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 70.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 71.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-cyclopentylurea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 449(M+H)⁺.

Compound 72.(R)-1-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 452(M+H)⁺.

Compound 73.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 451(M+H)⁺.

Compound 74.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methoxyphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 467(M+H)⁺.

Compound 75.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-fluorophenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 455(M+H)⁺.

Compound 76.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethylphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 77.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 505(M+H)⁺.

Compound 78.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 79.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(2-methoxyethyl)urea.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 439(M+H)⁺.

Compound 80.1. (R)-Tetrahydrofuran-3-yl 1H-imidazole-1-carboxylate. Asolution of (R)-tetrahydrofuran-3-ol (500 mg, 5.68 mmol, 1.00 equiv) andCDI (2 g, 12.33 mmol, 2.17 equiv) in tetrahydrofuran (50 mL) was stirredovernight under nitrogen at 60° C. After cooling to room temperature,the mixture was concentrated under reduced pressure. The residue wasdissolved in 30 mL of DCM and washed with 1×50 mL of H₂O. The organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:1) to yield 0.95 g (92%) of the titlecompound as a white solid.

Compound 80. (R)-Tetrahydrofuran-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)carbamate.A mixture of compound 42.2 (200 mg, 0.57 mmol, 1.00 equiv),(R)-tetrahydrofuran-3-yl 1H-imidazole-1-carboxylate (80.1, 12.4 mg, 0.68mmol, 1.20 equiv), and DBU (2.6 mg, 0.02 mmol, 0.03 equiv) in DMF (50mL) was stirred for 16 h under nitrogen at 120° C. After cooling toambient temperature, the reaction was quenched by the addition of 200 mLof water. The resulting mixture was extracted with 3×100 mL of ethylacetate. The combined organic layers were washed with 1×100 mL of brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue (200 mg) was purified by Prep-HPLC with thefollowing conditions (1 #-Pre-HPLC-002 (Agilent)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH₃CN (40.0%CH₃CN up to 45.0% in 8 min, hold 45.0% in 2 min, up to 100.0% in 1 min,down to 40.0% in 2 min); Detector, uv 220 254 nm. 47.4 mg product wasobtained. The fractions containing pure compound were combined andlyophilized to yield 47.4 mg (18%) of the title compound as a whitesolid. m/z (ES+) 466 (M+H)⁺.

Compound 81. 1-Acetylpyrrolidin-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)carbamate.The title compound was synthesized in a similar manner to that describedfor compound 80 to yield a white solid (113 mg, 39%). m/z (ES+) 507(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.80 (d, J=8.1 Hz, 2H), 7.77-7.61 (m,2H), 7.52 & 7.33 (2 br singlets, amide rotamers, Ar—H, 1H), 7.17 (s,1H), 5.41-5.28 (m, 1H), 4.87-4.72 (m, 1H), 3.88-3.42. (m, 6H), 3.33-3.19(m, 1H), 2.42-1.82 (m, 15H).

Compound 82. (R)-Tetrahydrofuran-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)carbamate.The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 80. m/z (ES+) 452(M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 1 and2:

Cmpnd m/z # Compound Name Compound Structure (ES+) 83 2-(5-(4-(4-cyanophenyl)piperidine- 1-carbonyl)-2,4- dimethylphenyl)-N,N-dimethyl-6,7- dihydro-3H- imidazo[4,5- c]pyridine-5(4H)- carboxamide

511 (M + H )⁺ 84 4-(2-(2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)benzoyl)piperidin- 4-yl)-N,N- dimethylbenzamide

487 (M + H)⁺ 85 (2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)phenyl)(4-(4- fluorophenyl)piperidin- 1-yl)methanone

434 (M + H)⁺ 86 (2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)phenyl)(4-(4- (methylsulfonyl)phen- yl)piperidin-1-yl)methanone

494 (M + H)⁺ 87 (2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)phenyl)(4-(4- methoxyphenyl)piperi- din-1-yl)methanone

446 (M + H)⁺ 88 1-(2-(2,4-dimethyl-5- (4-(4- (trifluoromethyl)phen-yl)piperidine-1- carbonyl)phenyl)-6,7- dihdyro-3H- imidazo[4,5-c]pyridin-5(4H)- yl)ethanone

525 (M + H)⁺ 89 4-(1-(5-(5- (cyclopropanecarbon- yl)-4,5,6,7-tetahydro-3H- imidazo[4,5- c]pyridin-2-yl)-2,4- dimethylbenzoyl)piperi-din-4- yl)benzonitrile

508 (M + H)⁺ 90 1-(2-(5-(4-(4- fluorophenyl)piperidine- 1-carbonyl)-2,4-dimethylphenyl)-6,7- dihydro-3H- imidazo[4,5- c]pyridin-5(4H)-yl)ethanone

475 (M + H)⁺ 91 4-(1-(4-methoxy-2- methyl-5-(3,4,6,7-tetrahydropyrano[3,4- d]imidazol-2- yl)benzoyl)piperidin-4-yl)benzonitrile

457 (M + H)⁺ 92 4-(4- fluorophenyl)piperidin- 1-yl)(5-(5-(isopropylsulfonyl)- 4,5,6,7-tetrahydro- 3H-imdazo[4,5-c]pyridin-2-yl)-2,4- dimethylphenyl)meth- anone

539 (M + H)⁺ 93 1-(2-(5-(4-(4- fluorophenyl)piperidine- 1-carbonyl)-2,4-dimethylphenyl)-6,7- dihydro-3H- imidazo[4,5- c]pyridin-5(4H)-yl)-2-methylpropan-1- one

503 (M + H)⁺ 94 (2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]pimidazol-2- yl)phenyl)(4- phenylpiperidin-1- yl)methanone

416 (M + H)⁺ 95 methyl 2-(5-(4-(4- cyanophenyl)piperidine-1-carbonyl)-2,4- dimethylphenyl)-6,7- dihydro-3H- imidazo[4,5-c]pyridin-5(4H)- carboxylate

498 (M + H)⁺ 96 4-(1-(2,4-dimethyl-5- (5-propionyl-4,5,6,7-tetahydro-3H- imidazo[4,5- c]pyridin-2- yl)benzoyl)piperidin-4-yl)benzonitrile

496 (M + H)⁺ 97 4-(1-(5-(5-isobutyryl- 4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridin-2-yl)-2,4- dimethylbenzoyl)piperi- din-4-yl)benzonitrile

510 (M + H)⁺ 98 (2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)phenyl)(4-(p- tolyl)piperidin-1- yl)methanone

430 (M + H)⁺ 99 4-(1-(2,4-dimethyl-5- (4,5,6,7-tetrahydro- 1H-benzo[d]imidazol-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

439 (M + H)⁺ 100 4-(1-(2,3-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

441 (M + H)⁺ 101 4-(1-(2-chloro-3- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

447 (M + H)⁺ 102 4-(1-(3-(5-isopropyl- 4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridin-2-yl)-4- methylbenzoyl)piperi-din-4-yl)benzonitrile

468 (M + H)⁺ 103 methyl 2-(5-(4-(4- cyanophenyl)piperidine-1-carbonyl)-2- methylphenyl)-6,7- dihdyro-3H- imidazo[4,5-c]pyridine-5(4H)- carboxylate

484 (M + H)⁺ 104 (2,4-dimethyl-5-(5- methyl-4,5,6,7- tetrahydro-3H-imdidazo[4,5- c]pyridin-2- yl)phenyl)(4-(4- (trifluoromethyl)phen-yl)piperidin-1- yl)methanone

497 (M + H)⁺

Compound 105.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 20,except compound 11.2 HCl salt was used in place of compound 1.5. m/z:(ES+) 523 (M+H)⁺.

Compound 106.4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 20,except 4-fluoro-2-methylbenzoic acid and azetidine were used in place of2,4-dimethylbenzoic acid and pyrrolidine respectively. m/z (ES+) 495(M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compound 20:

Cmpnd m/z # Compound Name Compound Structure (ES+) 107 2-(5-(4-(4-cyanophenyl)piperi- dine-1-carbonyl)- 2,4- dimethylphenyl)- 1H-benzo[d]imidazole- 5-carboxylic acid

479 (M + H)⁺ 108 4-(1-(5-(3H- imidazo[4,5- c]pyridin-2-yl)-2,4-dimethyl- benzoyl)piperidin-4- yl)benzonitrile

436 (M + H)⁺ 109 2-(5-(4-(4- cyanophenyl)piperi- dine-1-carbonyl)- 2,4-dimethylphenyl)- N,N-dimethyl-1H- benzo[d]imidazole- 5-carboxamide

506 (M + H)⁺ 110 2-(5-(4-(4- cyanophenyl)piperi- dine-1-carbonyl)- 2,4-dimethylphenyl)- 1H- benzo[d]imidazole- 5-carboxamde

478 (M + H)⁺ 111 2-(5-(4-(4- cyanophenyl)piperi- dine-1-carbonyl)- 2,4-dimethylphenyl)- 1H- benzo[d]imidazole- 5-carbonitrile

460 (M + H)⁺ 112 4-(1-(2,4-dimethyl- 5-(4-(oxetan-3-yl)- 3H-imidazo[4,5-c]pyridin-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

492 (M + H)⁺ 113 4-(1-(5-(4- methoxy-3H- imidazo[4,5-c]pyridin-2-yl)-2,4- dimethyl- benzoyl)piperidin-4- yl)benzonitrile

466 (M + H)⁺ 114 4-(1-(2,4-dimethyl- 5-(4-oxo-4,5- dihydro-3H-imidazo[4,5- c]pyridin-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

452 (M + H)⁺ 115 4-(1-(5-(4- (azetidin-1-yl)-3H- imidazo[4,5-c]pyridin-2-yl)-2,4- dimethyl- benzoyl)piperidin-4- yl)benzonitrile

491 (M + H)⁺ 116 4-(1-(2,4-dimethyl- 5-(6-(oxetan-3- yloxy)-3H-imidazo[4,5- c]pyridin-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

508 (M + H)⁺ 117 4-(1-(2,4-dimethyl- 5-(4-(pyrrolidin-1- yl)-3H-imidazo[4,5- c]pyridin-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

505 (M + H)⁺

Compound 118.1. Tetramethyl2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylate. A mixture of(E)-N-(4-methoxybenzylidene)-4-methylbenzenesulfonamide (2.89 g, 10mmol), dimethyl malonate (3.43 mL, 30 mmol), t-BuOK (2.24 g, 20 mmol) inanhydrous t-BuOH (20 mL) was heated at 50° C. for 4 h. After cooling toroom temperature, the reaction mixture was poured into saturated aqueousNH₄Cl and extracted with CH₂Cl₂ (3×). The combined organic layer wasdried over MgSO₄, filtered, and then concentrated. The residue waspurified by flash column chromatography with EtOAc in hexane (10%, 20%,30%, then 40%) to give the title compound as a clear oil (3.255 g, 85%yield).

Compound 118.2. 3-(4-Methoxyphenyl)pentanedioic acid and3-(4-hydroxyphenyl)pentanedioic acid. A mixture of tetramethyl2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylate (compound 118.1, 6.0g, 15.7 mmol) in concentrated HCl (37%, 80 mL) was heated under refluxovernight. After cooling to room temperature, the suspension wasfiltered. The filtrate was washed with water and dried under vacuum togive 2.66 g product as a mixture of 3-(4-methoxyphenyl)pentanedioic acid(major, LCMS observed [M−H]⁻ 237) and 3-(4-hydroxyphenyl)pentanedioicacid (minor, LCMS observed [M−H]⁻ 223).

Compound 118.3. Dimethyl 3-(4-methoxyphenyl)pentanedioate. A mixture ofthe product (compound 118.2) obtained from the previous step (2.66 g),K₂CO₃ (6.56 g, 47.5 mmol) and CH₃I (3 mL, 47.5 mmol) in DMF (10 mL) washeated at 50° C. in a pressure tube overnight. After cooling to roomtemperature, the reaction mixture was poured into saturated aqueousNaHCO₃ and extracted with EtOAc (3×). The combined organic extract wasdried over MaSO₄, filtered and concentrated. The residue was purified byflash column chromatography with EtOAc in hexane (20%, 30%, 40%, then50%) to give the title compound as a clear oil (2.0 g, 48% yield overtwo steps).

Compound 118.4. Dimethyl3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate. To a solution of LDA(18.8 mmol) in THF (60 mL) at −78° C. was added a solution of dimethyl3-(4-methoxyphenyl)pentanedioate (2.0 g, 7.52 mmol) in THF (10 mL)dropwise. After stirring at −78° C. for 1 h, the dry ice-acetone bathwas removed. The reaction mixture was stirred for 30 min before beingcooled to −78° C. Solid AgCl (2.2 g, 15.4 mmol) was added all at once.The reaction mixture was stirred at −78° C. for 1 h and then roomtemperature overnight. Saturated aqueous NH₄Cl was added. The mixturewas vigorously stirred for 10 min. The suspension was filtered throughcelite. The filtrate was extracted with EtOAc (3×). The combined organicextract was dried over MgSO₄, filtered, and concentrated. The residuewas purified by flash column chromatography with EtOAc in hexane (10%,15%, 20%, then 30%) to give the title compound as a pale yellow solid(0.87 g, 44% yield). ¹HNMR (CDCl₃, 400 Hz) δ 7.09 (d, J=8.8 Hz, 2H),6.86 (d, J=8.8 Hz, 2H), 3.82 (s, 3H), 3.77 (s, 6H), 3.17 (t, J=7.6 Hz,1H), 2.36 (d, J=7.6 Hz, 2H).

Compound 118.5. 3-(4-Methoxyphenyl)cyclopropane-1,2-dicarboxylic acid. Amixture of dimethyl3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate(0.88 g, 3.33 mmol) and LiOH (2M in H₂O, 10 mL) in THF (30 mL) wasstirred at 55° C. overnight. After cooling to room temperature, thereaction mixture was poured into 1N HCl and extracted with EtOAc (3×).The combined organic extract was dried over MgSO₄, filtered, andconcentrated to give the title compound as a light yellow solid.

Compound 118.6. 6-(4-Methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione.A mixture of 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid(crude product from the previous step) in Ac₂O (20 mL) was heated underreflux for 1 h. Excess Ac₂O was removed under reduced pressure. Thecrude product was used in the next step without further purification.

Compound 118.7.3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione.A mixture of 6-(4-Methoxyphenyl)-3-oxabicyclo[3,1.0]hexane-2,4-dione(crude product from the previous step) and (4-methoxyphenyl)methanaminewas heated at 180° C. for 1.5 h. After cooling to room temperature, thereaction mixture was dissolved in CH₂Cl₂ and purified by flash columnchromatography with EtOAc in hexane (20%, 30%, then 40%) to give thetitle compound as a yellow solid (0.71 g, 63% yield over three steps).MS [M+H]⁺: 338.

Compound 118.8.3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane. Amixture of3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(0.86 g, 2.6 mmol), NaBH₄ (0.296 g, 7.8 mmol) and BF₃ etherate (1.0 mL,7.8 mmol) in THF was heated under reflux overnight. After cooling to 0°C., a solution of piperazine (2 g) in H₂O (20 mL) was added. The mixturewas stirred at room temperature for 2 h, poured into H₂O and extractedwith EtOAc (3×). The combined organic extract was dried over MgSO₄,filtered and then concentrated. The residue was purified by flash columnchromatography with EtOAc in hexane (10%, 20%, then 30%) to give a whitesolid. To a suspension of the solid in THF (20 mL) and H₂O (10 mL) wasadded piperazine (3 g). After heating the mixture under refluxovernight, it was poured into brine and extracted with EtOAc (3×). Thecombined organic extract was dried over MgSO₄, filtered and concentratedto give the title compound as white solid (0.51 g, 65% yield). MS[M+H]⁺: 310.

Compound 118.9. 6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane. To asolution of(1R,5S,6S)-3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane(0.5 g, 1.6 mmol) in DCE (30 mL) at 0° C. was added 1-chloroethylchloroformate (0.21 mL, 1.9 mmol, 1.2 equiv). The reaction mixture wasstirred at 0° C. for 30 min, heated under reflux for 1 h and thenconcentrated under reduced pressure. MeOH (20 mL) was added. Theresulting mixture was heated under reflux for 40 min and thenconcentrated. The residue was purified by preparative TLC to give thetitle compound as a white crystalline solid (155 mg, 51% yield). MS[M+H]⁺: 190.

Compound 118.10.(3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone.A mixture of 6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane (0.124 g,0.82 mmol), 3-amino-4-methylbenzoic acid (0.155 g, 0.82 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.172g, 0.90 mmol), 1-hydroxybenzotriazole (˜20% H₂O, 0.122 g, 0.90 mmol) anddiisopropylethylamine (0.71 mL, 4.1 mmol) in DMF (3 mL) was stirred atroom temperature overnight. The reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted with EtOAc (3×). The combinedorganic extract was dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash column chromatography with EtOAc in hexane(60%, then 100%) to give the title compound as a white foam (0.15 g, 57%yield).

Compound 118.11.6-Chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide.To a solution of(3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone(150 mg, 0.47 mmol) and Et₃N (0.25 mL, 1.8 mmol) in CH₂Cl₂ (4 mL) at 0°C. was added 6-chloronicotinoyl chloride (106 mg, 0.6 mmol). The icebath was removed after the addition. The reaction mixture was stirred atroom temperature for 1.5 h and then purified by flash columnchromatography with EtOAc in hexane (60%, then 100%) to give the titlecompound as a white foam (0.172 g, 80% yield). MS [M+H]⁻: 462, 464.

Compound 118.6-(lsopropylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide.A mixture of6-chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide(compound 118.11, 0.107 g, 0.23 mmol) and isopropylamine (1.5 mL) inDMSO (1.5 mL) was heated at 120° C. in a sealed pressure tube overnight.After cooling to room temperature, the reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted with EtOAc (3×). The combinedorganic extract was dried over MgSO₄, filtered and concentrated. Theresidue was triturated with hexane to give the title compound as a whitepowder (40 mg, 36% yield). MS [M+H]⁺: 485. ¹H-NMR (DMSO-d6, 400 Hz) δ9.63 (s, 1H), 8.69 (d, J=3 Hz, 1H), 7.95-7.90 (m, 1H), 7.55-7.51 (m,1H), 7.39-7.30 (m, 2H), 7.10-7.03 (m, 3H), 6.84 (d, J=9.2 Hz, 2H), 6.52(d, J=9.2 Hz, 1H), 4.17-4.07 (m, 2H), 3.85-3.77 (m, 1H), 3.74 (s, 3H),3.65-3.51 (m, 2H), 2.30 (s, 3H), 1.87 (s, 2H), 1.69 (t, J=3.7 Hz, 1H),1.20 (d, J=7.2 Hz, 6H).

Compound 119.6-(Ethylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound118. MS [M+H]⁺: 471. ¹HNMR (DMSO-d6, 400 Hz) δ 9.62 (s, 1H), 8.66 (d,J=2.4 Hz, 1H), 7.91 (dd, J=2.4, 9.0 Hz, 1H), 7.50 (s, 1H), 7.34-7.24 (m,2H), 7.18 (t, J=6.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz,2H), 6.50 (d, J=9.2 Hz, 1H), 4.08 (d, J=12.4 Hz, 1H), 3.81-3.75 (m, 1H),3.70 (s, 3H), 3.59 (d, J=11.2 Hz, 1H), 3.52. (d, J=13.2 Hz, 1H),3.37-3.30 (m, 2H), 2.26 (s, 3H), 1.84 (s, 2H), 1.66 (t, 3.2 Hz, 1H),1.16 (t, J=8.4 Hz, 3H).

Compound 120.1-(5-6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compounds 64 and118. m/z (ES+) 436 (M+H)⁺.

Compound 121.1.4-(1-(3-Amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile. A solution of3-amino-4-methylbenzoic acid (1.36 g, 9.0 mmol),(4-(piperidin-4-yl)benzonitrile HCl salt (compound 1.5, 2.0 g, 9.0mmol), EDCI (1.89 g, 9.9 mmol), HOBT (1.66 g, 9.9 mmol, with 20% H₂O)and DIEA (3.13 ml, 18.0 mmol) in DMF (50 ml) was stirred at roomtemperature overnight. The reaction mixture was poured into cold water(300 ml) and off white solids precipitated. The precipitate wasfiltered, washed with water and dried under reduced pressure in an ovento yield 2.88 g (100%) of the title compound. m/z (ES+) 320 (M+H)⁺.

Compound 121.6-((5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)amino)-N-isopropylnicotinamide.A mixture of 6-chloro-N-isopropylnicotinamide (0.055 g, 0.26 mmol),4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (121.1, 0.1 g,0.31 mmol), K₂CO₃ (0.171 g, 1.24 mmol), Pd(OAc)₂ (6.7 mg, 0.03 mmol) andthe ligand (10.2 mg, 0.03 mmol) in toluene (5 mL) was heated at 90° C.under argon for 3 h. After cooling to room temperature, the reactionmixture was diluted with H₂O and extracted with EtOAc. The combinedorganic extract was dried over MgSO₄, filtered, and concentrated. Theresidue was purified by flash column chromatography with EtOAc in hexane(60%, 80%, then 100%) to give the title compound as an off-white powderafter lyophilization from CH₃CN/H₂O (11.2 mg, 9% yield). m/z (ES+) 482(M+H)⁺.

Compound 122.4-(1-(4-Methyl-3-((5-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)amino)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 121replacing K₂CO₃ with t-BuONa. m/z (ES+) 524 (M+H)⁺.

Compound 123.N-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)-6-(pyrrolidin-1-yl)nicotinamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 43and using 2-aminoisonicotinic acid in place of 3-amino-4-methylbenzoicacid. (ES+) 481 (M+H)⁺.

Compound 124.1-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)-3-isobutylurea.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 64and using 2-aminoisonicotinic acid in place of 3-amino-4-methylbenzoicacid. m/z (ES+) 406 (M+H)⁺.

Compound 125.N-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)pyrrolidine-1-carboxamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 64and using 2-aminoisonicotinic acid in place of 3-amino-4-methylbenzoicacid. m/z (ES+) 404 (M+H)⁺.

Compound 126.N-(3-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-(isopropylamino)nicotinamide.The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compound 43 andusing 3-amino-2,6-dimethylbenzoic acid in place of3-amino-4-methylbenzoic acid. m/z (ES+) 514 (M+H)⁺.

Compound 127.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2-ethyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 39.m/z (ES+) 445 (M+H)⁺.

Compound 128.4-(1-(3-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 38). m/z (ES+) 416 (M+H)⁺.

Compound 129.4-(1-(3-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 38.m/z (ES+) 402 (M+H)⁺.

Compound 130.1. Methyl 5-carbamothioyl-2,4-dimethylbenzoate. To around-bottom flask was added a solution of methyl5-cyano-2,4-dimethylbenzoate (compound 2.3, 1.78 g, 9.41 mmol, 1.00equiv) in tetrahydrofuran/H₂O (30/3 mL). O,O′-diethyl dithiophosphate(3.30 g, 17.7 mmol, 2.00 equiv) was added and the resulting mixture wasstirred for 2 days at 85° C. (CAUTION: significant gas evolutionoccurs—this and all other reactions described herein should be carriedout in well ventilated fume hoods). After cooling to ambienttemperature, the mixture was extracted with 2×50 mL of ethyl acetate.The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The crude residue was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:10) aseluent to furnish 1.20 g (57%) of the title compound as a yellow solid.

Compound 130.2. Methyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate.To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound130.1, 3.10 g, 12.5 mmol, 1.00 equiv, 90%) in tetrahydrofuran (30 mL)was added CH₃I (3.95 g, 27.8 mmol. 2.00 equiv) and the resulting mixturewas stirred overnight at 25° C. The organic layer was washed with 2×30mL of Na₂S₂O₄ (aq.) and 1×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. This resulted in 2.10 g (64%) ofmethyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate as a yellow oil.

Compound 130.3. Methyl 2-(tetrahydrofuran-3-yl)acetate. A mixture of of2-(tetrahydrofuran-3-yl)acetic acid (2.00 g, 15.4 mmol, 1.00 equiv) andsulfuric acid (2 mL) in methanol (20 mL) was stirred for 3 h at 80° C.in an oil bath. After cooling to ambient temperature, the mixture wasdiluted with 50 mL of ether and washed with 2×20 mL of water, 2×20 mL ofsodium bicarbonate (aq., sat. Note: gas evolution), and 2×20 mL ofbrine. The organic phase was then dried over anhydrous sodium sulfateand concentrated in vacuo to yield 1.50 g (68%) of the title compound asa yellow oil.

Compound 130.4. 2-(Tetrahydrofuran-3-yl)acetohydrazide. To around-bottom flask was added a solution of methyl2-(tetrahydrofuran-3-yl)acetate (compound 130.3, 1.50 g, 10.4 mmol, 1.00equiv) and NH₂NH₂.H₂O (1.04 g, 20.8 mmol, 2.00 equiv) in methanol (15mL). The resulting mixture was stirred overnight at 80° C. in an oilbath. After cooling to ambient temperature, the mixture was concentratedin vacuo to yield 1.20 g (80%) of the title compound as a yellow oil.

Compound 130.5. Methyl2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate.To a round-bottom flask was added a solution of2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4, 1.20 g, 8.32mmol, 1.50 equiv) in acetic acid (4 mL). Methyl2,4-dimethyl-5-(methylsulfanyl) carboximidoylbenzoate (compound 130.2,1.30 g, 5.48 mmol, 1.00 equiv) was added and the resulting mixture wasstirred overnight at 100° C. in an oil bath. After cooling to ambienttemperature, the mixture was concentrated in vacuo. The residue wasdiluted with 50 mL of ethyl acetate, then washed with 2×20 mL of waterand 2×20 mL of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography with ethyl acetate/petroleum ether(0:1-1:10-1:1) as eluent to furnish 0.600 g (35%) of the title compoundas a yellow solid.

Compound 130.6.2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoicacid. To a round-bottom flask was added a solution of methyl2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate(compound 130.5, 600 mg, 1.90 mmol, 1.00 equiv) in methanol (10 mL). Asolution of sodium hydroxide (381 mg, 9.53 mmol, 5.00 equiv) in water (5mL) was added and the resulting mixture was stirred for 3 h at 70° C. inan oil bath. After cooling to room temperature, the organic solvent wasthen removed under reduced pressure and the pH of the remaining aqueousphase was adjusted to 3-4 with hydrogen chloride (aq., 1 M). Theresulting solids were collected via filtration and dried in an ovenunder reduced pressure to yield 0.500 g (87%) of the title compound as ayellow solid.

Compound 130.4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.A mixture of compound 130.6 (200 mg, 0.660 mmol, 1.00 equiv), EDCI (253mg, 1.32 mmol, 2.00 equiv), DMAP (243 mg, 1.99 mmol, 3.00 equiv), and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 148 mg,0.660 mmol, 1.00 equiv) in DMF (5 mL) was stirred for 3 h at 25° C.,then diluted with 50 mL of ethyl acetate. The organic layer was washedwith 2×10 mL of water, 2×10 mL of brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. The crude product (˜300 mg) waspurified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase,water with 0.05% TFA and CH₃CN (28% CH₃CN up to 52% in 8 min, up to 100%in 1 min, down to 28% in 1 min); Detector, Waters 2489 254 & 220 nm. Thefractions containing pure compound were combined and lyophilized toyield 168 mg (52%) of the title compound as a white solid. m/z (ES+) 470(M+H)⁺. ¹H-NMR (400 Hz, CD₃OD): δ 7.68 (d, J=8.0 Hz, 2H), 7.61 (s, 1H),7.50-7.49 (m, 2H), 7.33-7.31 (m, 1H), 4.90-4.88 (m, 1H), 3.95-3.92 (m,2H), 3.90-3.81 (m, 1H), 3.79-3.77 (m, 1H), 3.69-3.55 (m, 1H), 3.28-3.25(m, 1H), 3.03-2.94 (m, 4H), 2.81-2.73 (m, 1H), 2.53 (s, 3H), 2.43 and2.33 (2s, amide rotamers, ArCH₃, 3H), 2.19-2.15 (m, 1H), 2.13-2.05 (m,1H), 1.94-1.68 (m, 4H).

Compound 131.4-(1-(5-(5-(2-Methoxyethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 3-methoxypropanehydrazide (compound 143.1) insteadof 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)444 (M+H)⁺.

Compound 132.4-(1-(5-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-methoxyacetohydrazide (compound 190.6) insteadof 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)430 (M+H)⁺.

Compound 133.1. (R)-Tetrahydrofuran-2-carbohydrazide. A mixture of(R)-tetrahydrofuran-2-carboxylic acid (5.00 g, 43.1 mmol, 1.00 equiv),EDCI (12.4 g, 64.6 mmol, 1.50 equiv) and HOBt (8.70 g, 64.4 mmol, 1.50equiv) in dichloromethane (100 mL) was stirred for 30 min at 25° C. Tothe mixture was then added hydrazine (2.00 g, 62.4 mmol, 1.50 equiv)dropwise. The resulting mixture was stirred overnight at 25° C. Thesolids were removed by filtration, and the filtrate was concentrated inmew) to furnish 25.0 g (crude) of (R)-tetrahydrofuran-2-carbohydrazideas a yellow oil.

Compound 133.(R)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using (R)-tetrahydrofuran-2-carbohydrazide (compound133.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 446 (M+H)⁺.

Compound 134.1. Ethyl 2-hydrazinyl-2-oxoacetate. To a round-bottom flaskwas added a solution of diethyl oxalate (10.0 g, 68.4 mmol, 1.00 equiv)in ethanol (100 mL). Hydrazine hydrate (2.75 g, 85.8 mmol, 1.00 equiv)was added and the resulting mixture was stirred for 3 h at 80° C. Aftercooling to ambient temperature, the solids were removed via filtrationand the filtrate was concentrated in vacuo to yield 8.00 g (80%) of thetitle compound as a colorless oil.

Compound 134.2. 2-Hydrazinyl-N-methyl-2-oxoacetamide. To a round-bottomflask was added a solution of ethyl 2-hydrazinyl-2-oxoacetate (compound134.1, 300 mg, 2.04 mmol, 1.00 equiv, 90%) in methanol (10 mL). Methylamine (10 mL, 40% in water) was added and the resulting mixture wasstirred overnight at 70° C. After cooling to ambient temperature, thesolids were collected by filtration and dried to yield 250 mg (94%) ofthe title compound as a white solid.

Compound 134.5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-4H-1,2,4-triazole-3-carboxamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound130, using compound 134.2 instead of compound 130.4. m/z (ES+) 443(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d, J=8.1 Hz, 2H), 7.62-7.43 (m,3H), 7.32 (s, 1H), ˜4.9 (1H partially obscured by water peak), 3.73-3.58(m, 1H), 3.32-3.18 (m, 1H partially obscured by methanol solvent peak),3.07-1.91 (m, 5H), 2.58 (s, 3H), 2.43 & 2.33 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.10-1.93 (m, 1H), 1.93-1.52 (m, 3H).

Compound 135.1, 2-Hydrazinyl-N,N-dimethyl-2-oxoacetamide. To around-bottom flask was added ethyl 2-hydrazinyl-2-oxoacetate (compound134.1. 2.00 g, 13.6 mmol, 1.00 equiv, 90%). Dimethylamine (10 mL) wasadded to the reaction, and then the reaction was stirred overnight at70° C. in an oil bath. The mixture was cooled to room temperature andconcentrated in vacuo to yield 1.50 g (76%) of the title compound as acolorless oil.

Compound 135.5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-hydrazinyl-N,N-dimethyl-2-oxoacetamide (compound135.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 457 (M+H)⁺.

Compound 136.1. (S)-Tetrahydrofuran-2-carbohydrazide. To a round-bottomflask was added a solution of (S)-tetrahydrofuran-2-carboxylic acid(3.00 g, 23.3 mmol, 1.00 equiv, 90%) in dichloromethane (40 mL). NH₂NH₂(2 mL, 2.00 equiv), HOBt (5.20 g, 38.5 mmol, 1.50 equiv), and EDCI (7.50g, 39.1 mmol, 1.50 equiv) were added and the resulting mixture wasstirred overnight at 25° C. The solids were removed by filtration, andthe filtrate was concentrated in vacuo to furnish 2.50 g (74%) of(S)-tetrahydrofuran-2-carbohydrazide as a yellow oil.

Compound 136.(S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using (S)-tetrahydrofuran-2-carbohydrazide (compound136.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 456 (M+H)⁻.

Compound 137.1. Methyl tetrahydro-2H-pyran-4-carboxylate. To a solutionof tetrahydro-2H-pyran-4-carboxylic acid (520 mg, 4.00 mmol, 1.00 equiv)in methanol (50 mL) was added PTSA (35.0 mg, 0.200 mmol). The resultingmixture was stirred overnight at 80° C. in an oil bath, then cooled toambient temperature and concentrated in vacuo. The residue was dilutedwith 30 mL of water and extracted with 3×30 mL of DCM. The combinedorganic layers were dried over anhydrous magnesium sulfate andconcentrated in vacuo. This resulted in 500 mg (87%) of methyltetrahydro-2H-pyran-4-carboxylate as a colorless oil.

Compound 137.2. Tetrahydro-2H-pyran-4-carbohydrazide. To a round-bottomflask was added a solution of methyl tetrahydro-2H-pyran-4-carboxylate(compound 137.1, 5.00 g, 31.2 mmol, 1.00 equiv, 90%) in methanol (50mL). Hydrazine hydrate (5.20 g, 83.2 mmol, 3.00 equiv) was added and theresulting mixture was stirred overnight at 40° C. in an oil bath. Aftercooling to ambient temperature, the mixture was concentrated in vacuo toyield 4.00 g (80%) of tetrahydro-2H-pyran-4-carbohydrazide as a whitesolid.

Compound 137.4-(1-(2,4-Dimethyl-5-(5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using tetrahydro-2H-pyran-4-carbohydrazide (compound137.2) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 470 (M+H)⁺.

Compound 138.1. 2-(Tetrahydrofuran-2-yl)acetohydrazide. To around-bottom flask was added a solution of ethyl2-(tetrahydrofuran-2-yl)acetate (2.00 g, 12.6 mmol, 1.00 equiv) inethanol (20 mL). NH₂NH₂.H₂O (1.27 g, 25.4 mmol, 2.00 equiv) was added tothe reaction. The resulting solution was stirred overnight at 80° C. inan oil bath, then cooled to room temperature and concentrated in vacuo.This resulted in 2.10 g (92%) of 2-(tetrahydrofuran-2-yl)acetohydrazideas a yellow oil.

Compound 138.4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-2-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-(tetrahydrofuran-2-yl)acetohydrazide (compound138.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 470 (M+H)⁺.

Compound 139.1. 2-Cyanoacetohydrazide. To a a solution of NH₂NH₂.H₂O(3.50 g, 70.0 mmol, 1.00 equiv) in a solvent mixture of ethanol and Et₂O(35/35 mL) at 0° C. was added dropwise a solution of methyl2-cyanoacetate (7.00 g, 70.6 mmol, 1.00 equiv) in ethanol (5 mL). Theresulting mixture was stirred for 3 h at room temperature, then washedwith 2×30 mL of ether. The solids were collected by filtration to yield5.00 g (68%) of 2-cyanoacetohydrazide as a white solid.

Compound 139.4-(1-(5-(5-(cyanomethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-cyanoacetohydrazide (compound 139.1) instead of2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 425(M+H)⁺. ¹H-NMR (300 Hz, CD₃OD): δ 7.70 (d, J=8.4 Hz, 2H), 7.54-7.42 (m,3H), 7.35 (s, 1H), 4.87-4.80 (m, 1H), 4.12 (s, 2H), 3.77-3.65 (m, 1H),3.27-3.23 (m, 1H), 3.09-2.99 (m, 2H), 2.55 (s, 3H), 2.43 and 2.33 (2singlets, amide rotamers, ArCH₃, 3H), 2.05-2.00 (m, 1H), 1.83-1.76 (m,3H).

Compound 140.1. 3-cyanopropanehydrazide. To a round-bottom flask wasadded a solution of NH₂N₂.H₂O (1.25 g, 25.1 mmol, 1.00 equiv) inether/EtOH (8/8 mL). To this was added methyl 3-cyanopropanoate (2.84 g,25.1 mmol, 1.00 equiv) dropwise. The resulting solution was stirred for2 h at room temperature, then concentrated in vacuo. This resulted in1.40 g (49%) of 3-cyanopropanehydrazide as a colorless oil.

Compound 140.4-(1-(5-(5-(2-cyanoethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 3-cyanopropanehydrazide (compound 140.1) insteadof 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)439 (M+H)⁺. ¹H-NMR (300 Hz, CD₃OD): δ 7.68 (d, 2H), 7.58-4.47 (m, 3H),7.30 (s, 1H), 4.89-4.80 (m, 1H), 3.65-3.62 (m, 1H), 3.32-3.30 (m, 1H),3.15 (t, 2H), 3.03-2.95 (m, 4H), 2.50 (s, 3H), 2.42 and 2.32 (2singlets, amide rotamers, ArCH₃, 3H), 2.03-2.00 (m, 1H), 1.83-1.78 (m,3H).

Compound 141.4-(1-(2,4-Dimethyl-5-(5-(oxetan-3-ylmethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130). m/z (ES+) 456 (M+H)⁺.

Compound 142.1. Methyl 4-cyclopropyl-2-methylbenzoate. To a solution ofmethyl 4-bromo-2-methylbenzoate (5.00 g, 20.7 mmol, 1.00 equiv, 95%) ina mixture of toluene and H₂O (2.0 mL/1 mL) were added potassiumcarbonate (6.10 g, 44.1 mmol, 2.00 equiv), cyclopropylboronic acid (2.30g, 26.8 mmol, 1.20 equiv), Pd(dppf)Cl₂ (900 mg, 1.23 mmol, 0.05 equiv),and Pd(OAc)₂ (250 mg, 1.12 mmol, 0.05 equiv). The reaction mixture waspurged with nitrogen and stirred at 80° C. overnight. After cooling toroom temperature, the mixture was then concentrated in vacuo. Theresulting residue was purified via silica gel column chromatography withethyl acetate/petroleum ether (1:50) as eluent to yield 2.68 g (61%) ofmethyl 4-cyclopropyl-2-methylbenzoate as a colorless oil.

Compound 142.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate. To asolution of methyl 4-cyclopropyl-2-methylbenzoate (compound 142.1, 2.68g, 13.4 mmol, 1.00 equiv, 95%) in AcOH (50 mL) were added NaIO₄ (1.51 g,7.08 mmol, 0.50 equiv), I₂ (3.58 g, 14.1 mmol, 1.00 equiv), and sulfuricacid (201 mg, 2.01 mmol, 0.15 equiv, 98%). The reaction mixture wasstirred at 110° C. overnight. After cooling to ambient temperature, 100mL of water was added. The resulting mixture was diluted with 100 mL ofethyl acetate, then washed with 3×30 mL of Na₂S₂O₃ (aq., sat.) and 1×30mL of brine. The organic phase was dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified via silica gelcolumn chromatography with ethyl acetate/petroleum ether (1/50) aseluent to yield 2.00 g (45%) of methyl4-cyclopropyl-5-iodo-2-methylbenzoate as a colorless oil.

Compound 142.3. Methyl 5-cyano-4-cyclopropyl-2-methylbenzoate. To asolution of methyl 4-cyclopropyl-5-iodo-2-methythenzoate (compound142.2, 2.00 g, 6.01 mmol, 1.00 equiv, 95%) in DMF (16 mL) was addedZn(CN)₂ (890 mg, 7.58 mmol, 1.27 equiv) and Pd(PPh₃)₄ (731 mg, 0.630mmol, 0.11 equiv). The resulting solution was stirred at 100° C. undernitrogen overnight. After cooling to ambient temperature, the reactionwas then quenched by the addition of 100 mL of FeSO₄ (aq., sat.) anddiluted with ethyl acetate. The resulting mixture was stirred vigorouslythen filtered through celite and washed with 1 M FeSO₄, water, and ethylacetate. The layers were separated and the aqueous phase was extractedwith 2×100 mL of ethyl acetate. The combined organic phases were driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified via silica gel column chromatography with ethylacetate/petroleum ether (1/50) as eluent to yield 1.10 g (81%) of methyl5-cyano-4-cyclopropyl-2-methylbenzoate as a light yellow oil.

Compound 142.4. Methyl 5-carbamothioyl-4-cyclopropyl-2-methylbenzoate.To a solution of methyl 5-cyano-4-cyclopropyl-2-methylbenzoate (compound142.3, 1.65 g, 7.28 mmol, 1.00 equiv, 95%) in a mixture oftetrahydrofuran and H₂O (20 mL/5 mL) was addedO,O′-diethylphosphorodithioate (3.79 g, 22.3 mmol, 2.00 equiv). Theresulting mixture was stirred at 80° C. overnight (CAUTION: significantgas evolution occurs—this and all other reactions described hereinshould be carried out in well ventilated fume hoods). After cooling toambient temperature, the reaction was quenched with 100 mL of water. Theresulting solution was extracted with 100 mL of ethyl acetate. Thecombined organic layers were washed with 3×30 mL of brine, dried overanhydrous sodium sulfate, and concentrated in vacuo. The residue waspurified via silica gel column chromatography with ethylacetate/petroleum ether (1/5) as client to furnish 0.880 g (46%) ofmethyl 5-carbamothioyl-4-cyclopropyl-2-methylbenzoate as a white solid.

Compound 142.5. Methyl4-cyclopropyl-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate. To around-bottom flask was added a solution of methyl5-carbamothioyl-4-cyclopropyl-2-methylbenzoate (compound 142.4, 880 mg,3.35 mmol, 1.00 equiv, 95%) in tetrahydrofuran (10 mL). lodomethane(1.00 g, 7.05 mmol, 2.00 equiv) was added and the resulting mixture andstirred at room temperature overnight. The mixture was then concentratedin vacuo to yield 0.800 g (86%) of methyl4-cyclopropyl-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate as acolorless liquid.

Compound 142.6. Methyl 3-(dimethylamino)propanoate hydrochloride. To around-bottom flask was added a solution of 3-(dimethylamino)propanoicacid (2.00 g, 17.1 mmol, 1.00 equiv) in methanol (60 mL). Hydrogenchloride (g) was bubbled into the reaction mixture and the resultingsolution was stirred for 4 h at 25° C. Concentration of the reactionmixture in vacuo afforded 2.00 g of title compound as a colorless oil.

Compound 142.7. 3-(Dimethylamino)propanehydrazide. To a solution ofmethyl 3-(dimethylamino)propanoate hydrochloride (compound 142.6, 2.00g, 15.3 mmol, 1.00 equiv) in methanol (40 mL) was added hydrazinehydrate (6 mL, 6.00 equiv). The reaction mixture was stirred at 70° C.for 3 h. The mixture was concentrated in vacuo and then dissolved in 50mL of H₂O and washed with 2×10 mL of ethyl acetate. The aqueous layerswere combined and concentrated in vacuo to afford 1.30 g (65%) of3-(dimethylamino)propanehydrazide as a colorless oil.

Compound 142.8. Methyl4-cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate.A solution of 3-(dimethylamino)propanehydrazide (compound 142.7, 1.20 g,9.15 mmol, 5.00 equiv) and methyl4-cyclopropyl-2-methyl-5-(methylsulfanyl) carboximidoylbenzoate(compound 142.5, 600 mg, 2.28 mmol, 1.00 equiv) in AcOH (30 mL) wasstirred at 80° C. overnight. After cooling to ambient temperature, thepH was adjusted to 8-9 with sodium hydroxide (aq., 1 M). The resultingmixture was extracted with 2×100 mL of ethyl acetate and the combinedorganic layers were concentrated in vacuo. The residue was purified viasilica column chromatography with dichloromethane/methanol (10/1) aseluent to give 504 mg (67%) of the title compound as a white solid.

Compound 142.9.4-Cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid. To a solution of compound 142.8 (200 mg, 0.610 mmol, 1.00 equiv)in a mixture of methanol and H₂O (6 mL/3 mL) was added sodium hydroxide(97.6 mg, 2.44 mmol, 4.00 equiv) in water (1 mL). After stirring at 60°C. overnight, the organic solvent was removed under reduced pressure.The residual aqueous layer was washed with 20 mL of ethyl acetate. ThepH was then adjusted to 4-5 with HCl (aq., 3 M), and the resultingmixture was extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried (Na₂SO₄) and concentrated in vacuo to afford 280 mg(73%) of the title compound as a brown solid.

Compound 142.4-(1-(4-Cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a solution of compound 2661.9 (250 mg, 0.800 mmol, 1.00 equiv) inN,N-dimethylformamide (3 mL) were added 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 175 mg, 0.790 mmol, 1.00 equiv), EDCI (302mg, 1.58 mmol, 2.00 equiv), and DMAP (194 mg, 1.59 mmol, 2.00 equiv).The resulting mixture was stirred at 25° C. overnight and then dilutedwith water. The mixture was extracted with 3×50 mL of ethyl acetate. Thecombined organic layers were washed with 2×20 mL of NH₄Cl (aq) and 2×20mL of brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified via silica gel column chromatographywith dichloromethane/methanol (10/1) as eluent. The product (˜150 mg)was further purified by Prep-HPLC with the following conditions[(1#-Pre-HPLC-001 (SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150mm; mobile phase, water with 0.03% NH₃H₂O and CH₃CN (32.0% CH₃CN up to47.0% in 7 min, up to 100.0% in 1 min, down to 32.0% in 1 min);Detector, Waters 2489 254 & 220 nm]. The fractions containing purecompound were combined and lyophilized to yield 70.3 mg (18%) of thetitle compound as a white solid. m/z (ES+) 483 (M+H)⁺.

Compound 143.1. 3-Methoxypropanehydrazide. A mixture of methyl3-methoxypropanoate (5.0 g, 42.33 mmol) and hydrazine (1.36 g, 42.33mmol) was heated at 50° C. for two hours. The mixture was concentratedand dried under reduced pressure to give the product as a clear oil.Yield: 5.0 g, 100%. m/z (ES+) 119 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d)δ 7.86 (br, 1H), 4.05-3.71 (m, 2H), 3.63 (t, 2H), 3.34 (s, 3H), 2.42 (t,2H).

Compound 143.4-(1-(4-Cyclopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 142and using compound 143.1 in place of 142.7. m/z (ES+) 471 (M+H)⁺.

Compound 144.4-(1-(4-Cyclopropyl-5-(5-((dimethylamino)methyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound142. m/z (ES+) 469 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d, J=6.3 Hz,2H), 7.49 (d, 6.0 Hz, 2H), 7.47 & 7.39 (2 singlets, amide rotamers,Ar—H, 1H), 7.03 (s, 1H), ˜4.9 (1H partially obscured by water peak),3.74 (s, 3.72-3.57 (m, 1H), 3.32-3.22 (m, 1H partially obscured bymethanol solvent peak), 3.00 (t with fine structure, J=8.9 Hz, 2H),2.49-2.27 (m, 2H), 2.10-1.98 (m, 2H), 1.93-1.51 (m, 3H), 1.05-0.90 (m,2H), 0.79-0.64 (m, 2H).

Compound 145.4-(1-(5-(5-(Azetidin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound142. m/z (ES+) 481 (M+H)⁺.

Compound 146.2-(5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-methylphenyl)-4H-1,2,4-triazol-3-yl)-N,N-dimethylacetamide. The title compound was prepared usingstandard chemical manipulations and procedures similar to those used forthe preparation of compound 142. m/z (ES+) 497 (M+H)⁺.

Compound 147.1. Methyl 4-ethyl-2-methylbenzoate. To a stirred mixture ofZnBr₂ (4.50 g, 20.0 mmol, 2.00 equiv) in tetrahydrofuran (50 mL) undernitrogen at 0° C. was added EtMgBr (6.6 mL, 2.00 equiv, 3M in THF)dropwise. After stirring for 30 min at 0° C., the temperature waslowered to −78° C. and Pd(dppf)Cl₂ (1.08 g, 1.48 mmol, 0.30 equiv) wasadded followed by a solution of methyl 4-bromo-2-methyl benzoate(compound 152.1, 2.30 g, 10.0 mmol, 1.00 equiv) in tetrahydrofuran (20mL). The resulting mixture was stirred for 30 min at −78° C., warmed toroom temperature, and stirred overnight. The reaction mixture wascarefully quenched with 60 mL of NH₄Cl (aq.) and extracted with 3×50 mLof ethyl acetate. The combined organic phases were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:100-1:5) as eluentto furnish 1.50 g (84%) of methyl 4-ethyl-2-methylbenzoate as a brownoil.

Compound 147.2.4-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 142.9 and using compounds 147.1 and 143.1 instead ofcompounds 142.1.and 142.7.

Compound 147.4-(1-(4-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a solution of compound (147.2, 100 mg, 0.350 mmol, 1.00 equiv) in DMF(10 mL) under nitrogen were added EDCI (132 mg, 0.690 mmol, 2.00 equiv)and DMAP (85.0 mg, 0.700 mmol, 2.00 equiv). The resulting mixture wasstirred 30 min at 25° C. followed by the addition of4-(piperidin-4-yl)benzonitrile (compound 1.5, 129 mg, 2.77 mmol, 2.00equiv). The reaction mixture was stirred for 25 h at 25° C., thenquenched with 40 mL of ice water, and extracted with 3×50 mL of ethylacetate. The combined organic layers were washed with 1×50 mL of brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:100-1:1) as eluent. The crude product (50 mg)was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase,water with 0.03% NH₃H₂O and CH₃CN (33% CH₃CN up to 52% in 10 min, up to100% in 1 min, down to 33% in 1 min); Detector, Waters 2489 254 & 220nm. The fractions containing pure compound were combined and lyophilizedto yield 20.2 mg (12%) of the title compound as a white solid. m/z (ES+)458 (M+H)⁻.

Compound 148.4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation compound 147and using compound 11.2 HCl salt instead compound 1.5. m/z (ES+) 476(M+H)⁺.

Compound 149.4-(1-(5-(5-(Ethoxymethyl)-4H-1,2,4-triazol-3-yl)-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds147 and 148. m/z (ES+) 476 (M+H)⁺.

Compound 150.4-(1-(4-Ethyl-2-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 147). m/z (ES+) 470 (M+H)⁺.

Compound 151.4-(1-(4-Ethyl-5-(5-(isopropoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds147 and 148. m/z (ES+) 490 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.78 (d,2H). 7.69-7.34 (m, 4H), 4.82-4.78 (m, 1H), 4.72 (s, 2H), 3.80 (quintet,1H), 3.57-3.55 (m, 2H), 3.30-3.25 (m, 1H), 2.94 (q, 2H), 2.46 and 2.35(2 singlets, amide rotamers, ArCH₃, 3H), 2.35-2.1 (m, 3H), 2.0-1.95 (m,1H), 1.30 (d, 6H), 1.14 (t, 3H).

Compound 152.1. Methyl 4-bromo-2-methylbenzoate. To a solution of4-bromo-2-methylbenzoic acid (5.11 g, 23.8 mmol, 1.0 equiv) in methanol(25 mL) was added dropwise ulfuric acid (2.0 mL) over about 3 minutes(mildly exothermic). The resulting mixture was refluxed for 4 hours.After cooling to room temperature, the reaction mixture was carefullyquenched into saturated aqueous NaHCO₃ (100 mL) (note—significant gasevolution) and extracted with dichloromethane (200 mL×1 then 50 mL×1).The combined organic phases were washed with a mixture ofbrine/saturated NaHCO₃ (9:1)(50 mL), dried (Na₂SO₄), and concentratedunder reduced pressure to obtain the title compound as a colorless oil(5.28 g, 97%). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J=8.0 Hz, 1H), 7.42(d, J=1.6 Hz, 1H), 7.38 (dd, J=1.6 Hz, 1H), 3.89 (s, 3H), 2.58 (s, 3H).

Compound 152.2. Methyl 4-cyclobutyl-2-methylbenzoate. Cyclobutylzinc(II)bromide (50 ml, 0.5 M in THF, 25.0 mmol) was added to a mixture ofmethyl 4-bromo-2-methylbenzoate (compound 152.1, 5.2 g, 22.7 mmol) andPdCl₂(dppf)CH₂Cl₂ (1.85 g, 2.27 mmol). The mixture was degassed and theflask was filled with argon through a balloon. The mixture was heated at65° C. under argon for 24 hours. The mixture was cooled to 0° C. andquenched with water (10 ml). The mixture was diluted with EtOAc (200ml), washed with water then with brine. The EtOAc layer was dried(Na₂SO₄), concentrated under reduced pressure, and purified using column(silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 4.1 g,clear oil, 89.1%. ¹H NMR (400 MHz, Chloroform-d) δ 7.86 (d, 1H),7.12-7.02 (m, 2H), 3.88 (s, 3H), 3.59-3.48 (m, 1H), 2.59 (s, 3H), 2.35(m, 2H), 2.22-1.96 (m, 3H), 1.86-1.84 (m, 1H).

Compound 152.3. Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate.N-Iodosuccinimide (3.52 g, 15.6 mmol) was added portionwise to asolution of methyl 4-cyclobutyl-2-methylbenzoate (compound 152.2, 3.2 g,15.6 mmol.) in concentrated sulfuric acid (25 ml) at 0° C. The mixturewas stirred at 0° C. for 30 min and at RT for 2 hours. The mixtureturned very thick. The mixture was cooled to 0° C. again and MeOH (30ml) was added. The mixture was heated at 60° C. for 2 hours. Themethanol was removed under reduced pressure and the residue was pouredinto ice water (100 ml). The mixture was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, then aq. 1N NaHCO₃(note-significant gas evolution), dried (Na₂SO₄) and concentrated. Theresidue was purified using column (silica gel) chromatography(hexanes:EtOAc 30:1 to 20:1). Yield: 4.17 g, light yellow oil, 81%. ¹HNMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H),3.67-3.54 (m, 1H), 2.57 (s, 3H), 2.51-2.40 (m, 2H), 2.14-1.97 (m, 3H),1.82-1.79 (m, 1H).

Compound 152.4. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate. A mixtureof methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 4.17 g,12.64 mmol), Zn(CN)₂ (2.96 g, 25.21 mmol) and Pd(PPh₃)₄ (0.73 g, 0.63mmol) in DMF (30 ml) was degassed and the flask was filled with argonthrough a balloon. The mixture was heated at 100° C. under argonovernight. After cooling to ambient temperature, the mixture wasquenched with saturated aq. FeSO₄ (20 ml) and diluted with EtOAc (200ml). The greenish solid was removed by filtration through celite. Thefiltrate was partitioned between water and EtOAc. The EtOAc layer waswashed with brine, dried (Na₂SO₄), and concentrated. The residue waspurified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to20:1). Yield: 2.55 g, white solid, 88%. ¹H NMR (400 MHz, Chloroform-d) δ8.16 (s, 1H), 7.28 (s, 1H), 3.90 (s, 3H), 3.86-3.82 (m, 1H), 2.68 (s,3H), 2.55-2.45 (m, 2H), 2.27-2.04 (m, 3H), 1.89-1.87 (m, 1H).

Compound 152.5. Methyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate. Toa round-bottom flask were added methyl5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4, 3.63 g, 0.015mol), O,O′-diethyl dithiophosphate (10 mL) and water (1 mL). Thereaction mixture was heated to 80° C. for 3 hours (CAUTION: significantgas evolution occurs—this and all other reactions described hereinshould be carried out in well ventilated fume hoods). After cooling toroom temperature, the reaction mixture was partitioned between ethylacetate (50 mL) and water (50 mL). The combined organic layers werewashed successively with saturated aqueous NaHCO₃ (50 mL) and brine (50mL), dried over Na₂SO₄, and concentrated in vacuo. Purification by SiO₂flash chromatography (hexanes/ethyl acetate=80/20 to 50/50) affordedmethyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate as a yellow solid(3.06 g, 78% yield). m/z (ES+) 264 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ7.93 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H), 6.92 (s, 1H), 4.19 (m, 1H),3.89 (s, 3H), 2.64 (s, 3H), 2.40 (m, 2H), 2.29-2.15 (m, 2H), 2.12-2.00(m, 1H), 1.95-1.84 (m, 1H).

Compound 152.6. Methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate. To around-bottom flask was added methyl5-carbamothioyl-4-cyclobutyl-2-methylbenzoate (compound 152.5, 861 mg,3.27 mmol) in THF (10 mL). Iodomethane (912 mg, 6.42 mmol) was addeddropwise and the reaction mixture was stirred at room temperature for 7hours. The reaction mixture was concentrated in vacuo and purified bySiO₂ flash chromatography (ethyl acetate to ethyl acetate/methanol=95/5)to afford methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate as a yellowishoil (807 mg, 89% yield). m/z (:ES+) 278 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 7.67 (s, 1H), 7.40 (s, 1H), 3.88-3.71 (m, 4H), 2.57 (s, 3H),2.44 (s, 3H), 2.22-2.19 (m, 2H), 2.12 (m, 2H), 1.98-1.86 (m, 1H),1.82-1.70 (m, 1H).

Compound 152.7. Methyl4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate. To around-bottom flask were added methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate (compound152.6, 556 mg, 0.002 mol) and acetohydrazide (223 mg, 0.003 mol) in 6 mLacetic acid. The reaction mixture was heated to 90° C. for 3 hours.After cooling to room temperature, the reaction mixture was partitionedbetween water (50 mL) and ethyl acetate (50 mL). The organic layer waswashed with brine (2×50 mL), dried over Na₂SO₄, and concentrated invacuo. Purification via SiO₂ flash chromatography (hexanes/ethylacetate=50/50 to 30/70) afforded the title compound as a white solid(243 mg, 43% yield). m/z (ES+) 286 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ8.23 (s, 1H), 7.32 (s, 1H), 4.24-4.05 (m, 1H), 3.89 (s, 3H), 2.69 (s,3H), 2.54 (s, 3H), 2.23-2.20 (m, 2H), 2.16-2.05 (m, 2H), 2.05-1.88 (m,1H), 1.88-1.71 (m, 1H).

Compound 152.8. 4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid. To a solution of methyl4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate(compound 152.7, 240 mg, 0.842 mmol) in methanol (5 mL) was addedaqueous NaOH (6 mL, 1M). The resulting mixture was heated to 50° C. for6 hours. After cooling to ambient temperature, the reaction mixture wasacidified with 1N HCl to pH 2 and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, and concentrated in vacuo to afford4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid(260 mg, quantitative) as a white solid. m/z (ES+) 272 (M+H)⁺.

Compound 152.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.To a solution of4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid(compound 152.8, 260 mg, 0.95 mmol) in DMF (4 mL) were added4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5, 232 mg,1.045 mmol), EDC (272 mg, 1.425 mmol), HOBt (39 mg, 0.285 mmol), andDIEA (367.7 mg, 2.85 mmol). The resulting mixture was stirred at roomtemperature for 16 hours. The mixture was quenched with saturatedaqueous NaHCO₃ (20 mL) and extracted with ethyl acetate (2.×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification via SiO₂column chromatography (dichloromethane/methanol=95/5) afforded4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrileas a white solid (193 mg, 44% yield). m/z (ES+) 440 (M+H)⁺. ¹H NMR (300MHz, CD₃OD): δ 7.69 (d, J=5.4 Hz, 2H), 7.56-7.30 (m, 4H), 1 protonobscured by methanol solvent peak, 4.10-3.98 (m, 1H), 3.64 (t, J=10.7Hz, 1H), 3.33-3.21 (m, 1H), 3.00 (t, J=8.9 Hz, 2H), 2.58 (s, 3H), 2.48and 2.38 (2 singlets, amide rotamers, ArCH₃, 3H), 2.28-1.92 (m, 6H),1.92-1.55 (m, 4H). ¹H NMR (400 MHz, DMSO-d₆): δ 13.66 (s, 1H), 7.77 (d,J=8.0 Hz, 2H), 7.62-7.34 (m, 4H), 4.78-4.63 (m, 1H), 4.31 (br s, 1H),3.45 (br s, 1H), 3.15 (app t, J=12.3 Hz, 1H), 2.99-2.78 (m, 2H),2.44-1.80 (m, 12H), 1.80-1.37 (m, 4H).

Compound 153.4-(1-(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), but using 3-methoxypropanehydrazide (compound 143.1) inplace of acetohydrazide. m/z (ES+) 484 (M+H)⁺, 967 (2M+H)⁺. ¹H NMR (400MHz, Chloroform-d) δ 11.50-11.33 (br s, 1H), 7.66-7.44 (m, 3H),7.33-7.27 (m, 3H), 4.98 (d, 1H), 4.24-4.12 (m, 1H), 3.78 (t, 2H), 3.70(d, 1H), 3.44 (s, 3H), 3.14-3.03 (m, 3H), 2.90-2.75 (m, 2H), 2.42 and2.34 (2 singlets, amide rotamers, ArCH₃, 3H), 2.17 (d, 2H), 2.08-1.88(m, 3H), 1.84-1.51 (m, 5H).

Compound 154.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152) but using 2-methoxyacetohydrazide (compound 190.6) inplace of acetohydrazide. m/z (ES+) 470 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃):δ 12.15 (br s, 1H), 7.64-7.57 (m, 2H), 7.43 & 7.33 (2 singlets, amiderotamers, Ar—H, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 5.04-4.92 (m,1H), 4.65 (s, 2H), 4.18-4.03 (m, 1H), 3.63 (br d, J=13.2 Hz, 1H), 3.51(s, 3H), 3.08 (t with fine structure, J=12.8 Hz, 1H), 2.93-2.77 (m, 2H),2.38 & 2.30 (2 singlets, amide rotamers, ArCH₃, 3H), 2.25-1.84 (m, 6H),1.84-1.43 (m, 4H).

Compound 155.4-(1-(4-Cyclobutyl-5-(5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 152but using 2-hydroxyacetohydrazide in place of acetohydrazide. m/z (ES+)456 (M+H)⁺.

Compound 156.4-(1-(4-Cyclobut-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 153), using 4-(4-fluoropiperidin-4-yl)benzonitrilehydrochloride salt (compound 11.2 HCl salt) instead of4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5). m/z(ES+) 501.8 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 11.46 (br s, 1H),7.75-7.45 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 4.89 (br d,J=13.2 Hz, 1H), 4.28-4.15 (m, 1H), 3.79 (t, J=6.0 Hz, 2H), 3.70-3.45 (m,2H), 3.46 (s, 3H), 3.31-3.17 (m, 1H), 3.13 (t, J=6.0 Hz, 2H), 2.45 &2.38 (2 br singlets, amide rotamers, Ar—CH₃, 3H), 2.30-1,68 (m, 10H).

Compound 157.(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 153), using 4-(4-(trifluoromethyl)phenyl)piperidinehydrochloride salt instead of 4-(piperidin-4-yl)benzonitrilehydrochloride salt (compound 1.5). m/z (ES+) 527 (M+H)⁺. ¹H NMR (400MHz, Chloroform-d) δ 11.30-11.10 (br, 1H), 7.60-7.47 (m, 3H), 7.35-7.28(m, 3H), 5.10-4.93 (m, 1H), 4.24-4.13 (m, 1H), 3.78 (t, 2H), 3.70 (d,1H), 3.45 (s, 3H), 3.12 t, 2H), 3.15-3.05 (m, 1H), 2.90-2.75 (m, 2H),2.44 and 2.35 (2 singlets, amide rotamers, ArCH₃, 3H), 2.25-2.13 (m,2H), 2.13-1.85 (m, 4H), 1.87-1.66 (m, 4H).

Compound 158.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), using compound 11.2 HCl salt instead of compound 1.5.m/z (ES+) 458 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.66 (s, 1H), 7.66(d, 2H), 7.51 (d, 3H), 7.38 (s, 1H), 4.72 (d, 1H), 4.30 (br s, 1H), 3.46(br s, 1H), 3.16 (dd, 1H), 3.04-2.78 (m, 2H), 2.38 and 2.36 (2 singlets,amide rotamers, ArCH₃, 3H), 2.35-2.27 (m, 3H), 2.22-1.82 (m, 6H),1.81-1.56 (m, 3H).

Compound 159.(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 483 (M+H)⁺.

Compound 160.4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 152and using propionohydrazide instead of acetohydrazide. m/z (ES+) 454(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.75-7.43 (m, 3H), 7.40-7.17(m, 3H), 5.18-4.81 (m, 1H), 4.30-3.91 (m, 1H), 3.84-3.55 (m, 1H),3.21-2.99 (m, 1H), 2.92-2.69 (m, 4H), 2.40 and 2.32 (2 singlets, amiderotamers, ArCH₃, 3H), 2.25-1.84 (m, 7H), 1.83-1.42 (m, 3H), 1.32 (t,3H).

Compound 161.4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 472 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ7.79-7.57 (m, 2H), 7.57-7.18 (m, 4H), 4.86 (dd, 1H), 4.14 (s, 1H),3.62-3.40 (m, 4H), 3.22 (t, 1H), 2.77 (q, 2H), 2.31 & 2.41 (2 singlets,amide rotamers, 3H), 2.29-1.47 (m, 8H), 1.30 (t, 3H).

Compound 162.4-1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 468 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d⁶) δ 13.67(s, 1H), 7.77 (d, 2H), 7.49-7.47 (m, 3H), 7.36 (s, 1H), 4.72 (d, 1H),4.29 (s, 1H), 3.46 (d, 1H), 3.12 (m, 2H), 2.98-2.75 (m, 2H), 2.31 (d,3H), 2.23-1.81 (m, 6H), 1.83-1.36 (m, 4H), 1.31 (d, 6H).

Compound 163.4-(1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 486 (M+H)⁺.

Compound 164.1.4-(1(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.7 and using propionohydrazide instead of acetohydrazide.

Compound 164.2. Methyl4-cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate.Methyl 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate(compound 164.1, 87 mg, 0.29 mmol) was dissolved in methanol anddichloromethane (1:1 v/v) (6 ml). ((Trimethylsilyl) methyl) diazomethane(2.0 M in ether) (220 ul, 0.44 mmol) was added. The mixture was stirredfor 16 hours and quenched with HOAc (300 ul). The volatiles were removedin vacuo to afford an oil (85 mg). The residue was carried as crude ontothe next step without further purification. m/z (ES+) 314 (M+H)⁺.

Compound 164.4-(1-(4-Cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl) benzonitrile. The title compound (mixture of N-methylisomers) was prepared using standard chemical manipulations andprocedures similar to those used for preparation of compound 152 andusing compound 164.2 instead of compound 152.7. m/z (ES+) 468 (M+H)⁺.

Compound 165.4-(1-(4-Cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES) 494.0 (M+H)⁺.

Compound 166.4-(1-(4-Cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl) benzonitrile. The title compound was prepared usingstandard chemical manipulations and procedures similar to those used forpreparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 476 (M+H)⁺.

Compound 167.4-(1-(4-Cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for preparation of4-[1-[4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl]-4-piperidyl]benzonitrile(compound 152). m/z (ES+) 494 (M+H)⁺.

Compound 168.1. Methyl 4-cyclobutylbenzoate. To a stirred mixture ofZnBr₂ (83.0 g, 368.53 mmol, 4.00 equiv) in THF (500 mL) under nitrogenat 0° C. was added a solution of bromo(cyclobutyl)magnesium (242 mL, 364mmol, 1.5 M in THF) dropwise during 20 min. To the resulting mixturewere added Pd(dppf)Cl₂ (2.00 g, 0.10 equiv) and methyl 4-bromobenzoate(20 g, 93.00 mmol, 1.00 equiv) at −40° C. The resulting mixture wasstirred at −40° C. for 1 h under nitrogen, and then carefully quenchedwith 500 mL of NH₄Cl (aq., sat.). The mixture was extracted with 3×500mL of ethyl acetate. The combined organic layers were washed with 3×500mL of brine, then dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to yield 18.0 g (crude) of the title compound asa light yellow oil.

Compound 168.2. Methyl 4-cyclobutyl-3-iodobenzoate. To a solution ofmethyl 4-cyclobutylbenzoate (168.1, 2.00 g, 10.5 mmol, 1.00 equiv) inacetic acid (30 mL) were carefully added sodium periodate (1.00 g, 4.68mmol, 0.50 equiv), iodine (3.00 g, 11.8 mmol, 1.10 equiv) and sulfuricacid (0.15 g, 0.15 equiv). The resulting mixture was stirred overnightat 100° C. After cooling to room temperature, the reaction was thenquenched by carefully adding 30 mL of Na₂S₂O₃ (aq., sat.) and theresulting mixture was extracted with 3×20 mL of ethyl acetate. Thecombined organic layers were washed with 3×20 mL of brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toyield 1.50 g (45%) of the title compound as a yellow oil.

Compound 168.3. Methyl 3-cyano-4-cyclobutylbenzoate. The title compound(2.60 g (95%), white solid) was prepared using standard chemicalmanipulations and a procedure similar to that used for the preparationof compound 152.4 and using compound 168.2 (4.00 g, 12.7 mmol) in placeof compound 152.3.

Compound 168.4-(1-(4-Cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using procedures similar to those usedfor preparation of compound 152 and using 168.3 in place of 152.4. m/z(ES+) 458 (M+H)⁺.

Compound 169.4-(1-(4-Cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using procedures similar to those usedfor preparation of compound 152 and using 168.3 in place of 152.4. m/z(ES+) 440 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.88 (d, 2H), 7.67-7.50 (m,3H), 7.47 (d, 2H), 4.89-4.75 (m, 1H), 4.25-3.73 (m, 2H), 3.35-3.25 (m,1H), 3.16-2.75 (m, 4H), 2.30-1.94 (m, 6H), 1.93-1.56 (m, 4H), 1.51-1.32(m, 3H).

Compound 170.4-(1-(4-Cyclobutyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using procedures similar to those usedfor preparation of compound 152 and using compounds 168.3 and 11.2 HClsalt in place of compounds 152.4 and 1.5 respectively. m/z (ES+) 444(M+H)⁺.

Compound 171.4-(1-(4-Cyclobutyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using procedures similar to those usedfor preparation of compounds 152 and 156 and using 168.3 in place of152.4. m/z (ES+) 488 (M+H)⁺.

Compound 172.1. (S)-Tetrahydrofuran-2-carbohydrazide. To a round-bottomflask was added a solution of (S)-tetrahydrofuran-2-carboxylic acid(3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (40 mL). EDC.HCl(7.50 g, 39.1 mmol, 1.50 equiv), HOBT (5.20 g, 38.5 mmol, 1.50 equiv),and hydrazine hydrate (2 mL, 2.00 equiv, 99%) were added to thereaction. The resulting solution was stirred overnight at roomtemperature. The solids were removed by filtration and the filtrate waswas concentrated in vacuo to furnish 5.38 g (80%) of the title compoundas a yellow oil.

Compound 172.(S)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), using (S)-tetrahydrofuran-2-carbohydrazide (compound172.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)⁺.

Compound 173.(S)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using procedures similar to those usedfor the preparation of compound 172 and using compound 11.2 HCl salt inplace of compound 1.5. m/z (ES+) 514 (M+H)⁺.

Compound 174.1. (R)-Tetrahydrofuran-2-carbohydrazide. To a round-bottomflask was added a solution of (R)-tetrahydrofuran-2-carboxylic acid(3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (60 mL), EDC.HCl(7.37 g, 38.5 mmol, 1.50 equiv), HOBt (5.24 g, 38.8 mmol, 1.50 equiv),and hydrazine hydrate (2.60 g, 51.9 mmol, 2.00 equiv) were added to thereaction. The resulting solution was stirred overnight at 25° C. Thesolids were removed with filtration. The filtrate was concentrated invacuo to yield 2.00 g (59%) of (R)-tetrahydrofuran-2-carbohydrazide as ayellow oil.

Compound 174.(R)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), using (R)-tetrahydrofuran-2-carbohydrazide (compound174.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)⁺. ¹H NMR (300MHz, CD₃OD) δ 7.70 (d, 2H), 7.49-7.41 (m, 4H), 5.15 (t, 1H), 4.89-4.80(m, 1H), 4.14-3.92 (m, 3H), 3.65-3.51 (m, 1H), 3.33-3.27 (m, 1H),3.03-2.95 (m, 2H), 2.47-2.37 (m, 4H), 2.24-1.91 (m, 9H), 1.83-1.71 (m,4H).

Compound 175.1.4-Cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid.The title compound was synthesized using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.8 and using bromo(cyclopentyl)magnesium in place ofbromo(cyclobutyl)magnesium.

Compound 175.4-(1-(4-Cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was synthesized using a procedure similar to thatused for the preparation of compound 152 and using compound 175.1 inplace of compound 152.8. m/z (ES+) 495 (M+H)⁺.

Compound 176.1. tert-Butyl4-(4-bromophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate. The titlecompound was synthesized using a procedure similar to that used for thepreparation of compound 1.1 and using tert-butyl2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl4-oxopiperidine-1-carboxylate.

Compound 176.2. tert-Butyl4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate. The title compoundwas synthesized using procedures similar to those used for thepreparation of compound 1.4 and using compound 176.1 in place ofcompound 1.1.

Compound 176.3. 4-(2-Methylpiperidin-4-yl)benzonitrile. To a solution oftert-butyl 4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate (compound176.2, 500 mg, 1.50 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) wasadded TFA dropwise (1 mL). The resulting mixture was stirred for 1.5 hat room temperature, then diluted with 30 mL of dichloromethane. Theresulting mixture was washed with with sodium bicarbonate (aq., 1 M.Note: significant gas evolution). The aqueous phase was extracted with2×50 mL of dichloromethane and the combined organic layers were dried(Na₂SO₄), and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with methanol/dichloromethane(1:50-1:20) as eluent to yield 280 mg (93%) of4-(2-methylpiperidin-4-yl)benzonitrile as a colorless oil.

Compound 176.4. tert-Butyl4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate. The title compoundwas synthesized using a procedure similar to that used for thepreparation of compound 152.8 and using compound 164.1 in place ofcompound 152.7.

Compound 176.4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-2-methylpiperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of4-(2-methylpiperidin-4-yl)benzonitrile (compound 176.3, 210 mg, 0.940mmol. 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL). EDC HCl (404 mg,2.11 mmol, 2.00 equiv), 4-dimethylaminopyridine (257 mg, 2.10 mmol, 2.00equiv), and4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 176.4, 300 mg, 1.05 mmol, 1.00 equiv) were added to thereaction mixture. The resulting solution was stirred for 4 h at 25° C.,then diluted with 50 mL of ethyl acetate. The resulting mixture waswashed with 2×30 mL of NH₄Cl (aq., sat.) and 2×30 mL of brine, driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified using silica gel column chromatography withdichloromethane/methanol (20:1) as eluent. The crude product (˜20 mg)was further purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (48% CH₃CN up to 49% in 8min, up to 100% in 3 min, down to 48% in 2 min); Detector, Waters 2489254 & 220 nm. The fractions containing pure compound were combined andlyophilized to yield 3.8 mg (1%) of the title compound as a white solid.m/z (ES+) 468 (M+H)⁺.

Compound 177.1. 4-Chloro-5-iodo-2-methylbenzoic acid. To a round-bottomflask was added a solution of 4-chloro-2-methylbenzoic acid (30.0 g, 176mmol, 1.00 equiv) in acetic acid (300 mL). NaIO₄ (19.0 g, 88.8 mmol,0.50 equiv), I₂ (49.0 g, 193 mmol, 1.10 equiv), and sulfuric acid (3 mL)were added to the reaction. The resulting mixture was stirred overnightat 110° C. After cooling to ambient temperature, the reaction wascarefully quenched with 500 mL of Na₂S₂O₃ (aq., sat.). The resultingsolids were collected by filtration and then dissolved in 500 mL ofethyl acetate. The organic phase was washed with 2×200 mL of brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. This resulted in 20.0 g (38%) of4-chloro-5-iodo-2-methylbenzoic acid as a white solid.

Compound 177.2. Methyl 4-chloro-5-iodo-2-methylbenzoate. To a solutionof 4-chloro-5-iodo-2-methylbenzoic acid (compound 177.1, 20.0 g, 67.5mmol, 1.00 equiv) in methanol (100 mL) was added sulfuric acid (5 mL)dropwise. The resulting mixture was stirred overnight at 75° C. Aftercooling to ambient temperature, the methanol was removed under reducedpressure. The pH value of the remaining aqueous layer was carefullyadjusted to 7 with sodium bicarbonate (aq., 1 M. Note: significant gasevolution). The aqueous phase was extracted with 2×200 mL of ethylacetate and the combined organic layers were washed with 2×100 mL ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (1:50) as eluent to furnish 20.0 g(95%) of methyl 4-chloro-5-iodo-2-methylbenzoate as a light yellowliquid.

Compound 177.3.4-Chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 152.8 but using compounds 177.2 and 143.1 instead ofcompound 152.3 and acetoydrazide respectively.

Compound 177.4-(1-(4-Chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2methylbenzoyl)piperidin-4-yl)benzonitrile. The title compound wasprepared using standard chemical manipulations and procedures similar tothose used for the preparation of compound 152 but using compound 177.3instead of compound 152.8. m/z (ES+) 464 (M+H)⁺.

Compound 178.1. 2-Bromo-4-chlorobenzoate. The title compound (17.0 glight yellow solid, 80%) was prepared using a procedure similar to thatused for the preparation of compound 177.2 but using2-bromo-4-chlorobenzoic acid (20.0 g) in place of compound 177.1.

Compound 178.2. Methyl 4-chloro-2-ethylbenzoate. The title compound(2.20 g light colorless liquid, 55%) was prepared using a proceduresimilar to that used for the preparation of compound 48.1 but usingcompound 178.1 (5.00 g) in place of methyl 2-bromo-4-methylbenzoate.

Compound 178.3.4-Chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoicacid. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 152.8 using compound 178.2 and 3-methoxypropanehydrazide(compound 143.1) instead of compound 152.2 and acetoydraziderespectively.

Compound 178.4-(1-(4-Chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using a procedure similar to that usedfor the preparation of compound 152 but using compound 178.3 in place ofcompound 152.8. m/z (ES+) 478 (M+H)⁺.

Compound 179.4-(1-(4-Chloro-2-ethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 38and 178. m/z (ES+) 490 (M+H)⁺.

Compound 180.1. Methyl 4-bromo-2-fluorobenzoate. To a 500-mL three neckround-bottom flask was added a solution of 4-bromo-2-fluorobenzoic acid(30.0 g, 137 mmol, 1.00 equiv) in methanol (200 mL). SOCl₂ (24.0 g, 202mmol, 1.50 equiv) was added dropwise at 0° C. The resulting solution wasstirred for 10 min at 0° C., for 30 min at 25° C., and then for 3 h at50° C. After cooling to room temperature, the resulting mixture wasconcentrated under reduced pressure. The residue was partitioned betweenwater (100 mL) and ethyl acetate (100 mL). The aqueous phase wasextracted with 100 mL of ethyl acetate. The combined organic layers werewashed with 1×100 mL of water, 1×100 mL of sodium bicarbonate (aq. sat.)and 1×100 mL of brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to yield 30.0 g (94%) ofthe title compound as a light yellow solid.

Compound 180.2. Methyl 4-ethyl-2-fluorobenzoate. The title compound(3.80 g light colorless oil, 97%) was prepared using a procedure similarto that used for the preparation of compound 48.1 but using compound180.1 (5.00 in place of methyl 2-bromo-4-methylbenzoate.

Compound 180.3.4-Ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoicacid. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 152.8 using compounds 180.2 and 143.1 instead of compound152.2 and acetoydrazide respectively.

Compound 180.4-(1-(4-Ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 152but using compound 180.3 in place of compound 152.8. m/z (ES+) 462(M+H)⁺.

Compound 181.1. 4-Bromo-2-ethylbenzoic acid. To a 1 L three neckround-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added 4-bromo-2-fluorobenzoic acid (50.0 g, 228 mmol,1.00 equiv) in tetrahydrofuran (500 mL). A solution of ethylmagnesiumbromide (250 mL, 3 M in THF) was added dropwise at 0° C. The resultingsolution was stirred for 3-4 h at 0° C. The mixture was then carefullyquenched by dropwise addition of water at 0° C. After complete quench ofthe reaction, additional water was added and the pH was adjusted to 2-3with hydrogen chloride (aqueous, 2 M). The mixture was extracted with2×200 mL of ethyl acetate and the organic layers were combined. Sodiumhydroxide (2N, aq.) was employed to adjust the pH to 7-8. The resultingmixture was washed with 2×200 mL of ethyl acetate. The pH value of theaqueous solution was adjusted to 2-3 with 2N hydrogen chloride, thenextracted with 2×200 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo. Thisresulted in 30.0 g (57%) of 4-bromo-2-ethylbenzoic acid as a yellowsolid.

Compound 181.2. Methyl 4-bromo-2-ethylbenzoate. The title compound (25.0g light yellow liquid, 79%) was prepared using a procedure similar tothat used for the preparation of compound 177.2 but using compound 181.1(30.0 g) in place of compound 177.1.

Compound 181.3. Methyl 4-cyclobutyl-2-ethylbenzoate. To a stirredmixture of ZnBr₂ (33.5 g, 149 mmol, 4.00 equiv) in THF (350 mL) undernitrogen at 0° C. was added dropwise a solution of cyclobutylmagnesiumbromide (148 mmol in 50 mL THF). After stirring at 0° C. for 0.5 h, thetemperature was lowered to −78° C. and Pd(dppf)Cl₂ (2.00 g, 2.73 mmol,0.07 equiv) was added followed by the addition of a solution of methyl4-bromo-2-ethylbenzoate (compound 181.2, 9.00 g, 37.0 mmol, 1.00 equiv)in tetrahydrofuran (10 mL) dropwise at the same temperature. Thereaction mixture was slowly allowed to reach ambient temperature andthen stirred overnight. The reaction was carefully quenched with asaturated NH₄Cl aqueous solution (100 mL). The resulting mixture wasextracted with 500 mL of ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:50) to furnish 8.00 g (99%) of the desired product as a light yellowoil.

Compound 181.4. Methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate. To asolution of methyl 4-cyclobut-2-ethylbenzoate (compound 181.3, 7.70 g,35.3 mmol, 1.00 equiv) in acetic acid (80 mL) was added iodine (8.98 g,35.4 mmol, 1.00 equiv), NaIO₄ (3,78 g, 17.7 mmol, 0.50 equiv), andsulfuric acid (0.870 g, 8.87 mmol, 025 equiv). The reaction mixture wasstirred at 60° C. overnight. After cooling to room temperature, thereaction was slowly quenched with Na₂S₂O₃ (aq., sat.). The mixture wasextracted with 200 mL of ethyl acetate and the organic layer was driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:50) to furnish 10.5 g (86%) of the desired product as a colorlesssolid.

Compound 181.5. Methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate. To around-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of methyl4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 5.50 g, 16.0 mmol,1.00 equiv) in N,N-dimethylformamide (150 mL). Zinc cyanide (2.78 g,23.7 mmol, 1.50 equiv) and Pd(PPh₃)₄ (1.83 g, 1.59 mmol, 0.10 equiv)were added to the reaction mixture. The resulting solution was stirredat 100° C. for 15 h under nitrogen. After cooling to ambienttemperature, the reaction was carefully quenched with 300 mL ofFeSO₄(aq., sat.) and diluted with ethyl acetate. The resulting mixturewas stirred vigorously then filtered through celite and washed with 1 MFeSO₄, water, and ethyl acetate. The layers were separated and theaqueous phase was extracted with 2×300 mL of ethyl acetate. The combinedorganic layers were washed with 2×300 mL of brine, dried over anhydroussodium sulfate, and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography with ethyl acetate/petroleumether (1:100-1:50) as eluent to furnish 3.20 g (82%) of methyl5-cyano-4-cyclobutyl-2-ethylbenzoate as a light yellow oil.

Compound 181.6. Methyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate. Toa round-bottom flask was added a solution of methyl5-cyano-4-cyclobutyl-2-ethylbenzoate (compound 181.5, 3.00 g, 12.3 mmol,1.00 equiv) in a solvent mixture of tetrahydrofuran and H₂O (80 mL/40mL). To this was added O,O′-diethyl dithiophosphate (6.69 g, 35.9 mmol,3.00 equiv) dropwise with stirring. The resulting solution was stirredat 85° C. for 48 h (CAUTION: significant gas evolution occurs—this andall other reactions described herein should be carried out in wellventilated fume hoods). After cooling to ambient temperature, themixture was then concentrated in vacuo. The crude product was purifiedby re-crystallization from petroleum ether to furnish 1.30 g (38%) ofmethyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate as a light yellowsolid.

Compound 181.7. Methyl4-cyclobutyl-2-ethyl-5-(imino(methylthio)methyl)benzoate. To around-bottom flask was added a solution of methyl5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate (compound 181.6, 1.50 g,5.41 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). This was followed bythe addition of iodomethane (3.80 g, 26.8 mmol, 5.00 equiv) dropwisewith stirring. The resulting solution was stirred at 25° C. for 15 h,then concentrated in vacuo. This resulted in 1.80 g (97%) of the titlecompound as a yellow oil.

Compound 181.8. Methyl4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate. To around-bottom flask was added a solution of methyl4-cyclobutyl-2-ethyl-5-(methylsulfanyl)carboximidoylbenzoate (compound181.7, 900 mg, 3.09 mmol, 1.00 equiv) in AcOH (20 mL). Propionohydrazide(880 mg, 9.99 mmol, 3.00 equiv) was added and the resulting mixture wasstirred at 90° C. for 2 h. After cooling to ambient temperature, themixture was then concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:50-1:3) as eluent to give 0.360 g (37%) of the title compound as aclear oil.

Compound 181.9.4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid. To around-bottom flask was added a solution of methyl4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate (compound181.8, 360 mg, 1.15 mmol, 1.00 equiv) in methanol (20 mL). A solution ofsodium hydroxide (460 mg, 11.5 mmol, 10.0 equiv) in water (10 mL) wasadded to the reaction mixture. The resulting solution was stirred at 25°C. for 15 h. The organic solvent was then removed under reducedpressure. The pH value of the remaining aqueous phase was adjusted to2-3 with hydrogen chloride (aq., 2 M). The resulting precipitate wascollected by filtration and dried under high-vaccum to yield 320 mg(93%) of the title compound as a white solid.

Compound 181.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.To a solution of4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid(compound 181.9, 160 mg, 0.530 mmol, 1.00 equiv) inN,N-dimethylformamide (20 mL) were added EDCI (113 mg, 0.590 mmol, 1.11equiv), DMAP (197 mg, 1.62 mmol, 3.03 equiv), and HOBT (87.5 mg, 0.650mmol, 1.21 equiv). After 5 min, 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 110 mg, 0.590 mmol, 1.10 equiv) was added.The resulting mixture was stirred at 25° C. for 15 h, then quenched with100 mL of ice water. The mixture was extracted with 2×150 mL of ethylacetate. The combined organic layers were washed with 3×150 mL of brine,dried over anhydrous sodium sulfate, and concentrated. The crude product(˜150 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (47% CH₃CN up to 61% in 6min, up to 100% in 1.5 min, down to 47% in 1.5 min); Detector, Waters2489 254 & 220 nm. The fractions containing pure compound were combinedand lyophilized to yield 99.5 mg (40%) of the title compound as a whitesolid m/z (ES+) 468 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.71-7.69 (m,2H), 7.50-7.32 (m, 4H), 4.03-3.99 (m, 1H), 3.65-3.5 (m, 1H), 3.32-3.20(m, 1H), 2.90-2.95 (m, 4H), 2.70-2.74 (m, 2H), 2.20-1.98 (m, 6H),1.98-1.79 (m, 4H), 1.41 (t, 3H), 1.39-1.28 (m, 3H).

Compound 182.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 484 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.67 (d,2H), 7.49-7.37 (m, 3H), 7.11-7.05 (m, 1H), 4.89-4.80 (m, 1H), 3.81 (t,2H), 3.77-3.60 (m, 1H), 3.4 (s, 3H), 3.37-3.32 (m, 1H), 3.14 (t, 2H),3.15-2.9 (m, 2H), 2.92-2.5 (m, 2H), 2.39-2.36 (m, 1H), 2.02-1.85 (m,1H), 1.85-1.69 (m, 3H), 1.32-1.21 (m, 3H), 1.0-0.95 (m, 2H), 0.77-0.69(m, 2H).

Compound 183.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 470 (M+H)⁺.

Compound 184.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181 and using compound 11.2 HCl salt in place of compound 1.5.m/z (ES+) 502 (M+H)⁺.

Compound 185.4-(1-4-Cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 484 (M+H)⁺.

Compound 186.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 181and using compound 11.2 HCl salt in place of compound 1.5. m/z (ES+) 486(M+H)⁺.

Compound 187.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181 and using compound 11.2 HCl salt in place of compound 1.5.m/z (ES+) 516 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.77 (d, 2H), 7.66-7.47(m, 2H), 7.47-7.35 (m, 2H), 4.89-4.83 (m, 1H), 4.08-4.03 (t, 1H), 3.79(t, 2H), 3.55 (t, 2H), 3.33 (s, 3H), 3.28-3.20 (m, 1H), 3.12 (t, 2H),2.80-2.68 (m, 2H), 2.27-1.68 (m, 10H), 1.27 (t, 3H).

Compound 188.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 498 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.67 (d,2H), 7.44-7.31 (m, 4H), 489 (s, 1H), 4.04-3.98 (m, 1H), 3.79 (t, 2H),3.66-3.60 (m, 1H), 3.33 (s, 3H), 3.23-3.12 (m, 1H), 3.10 (t, 2H), 3.02(t, 2H), 2.77-2.66 (m, 2H), 2.19-2.04 (m, 6H), 1.80-1.68 (m, 4H),1.31-1.26 (m, 3H).

Compound 189.1. Methyl 4-(cyclobutylmethyl)-2-methylbenzoate. The titlecompound (4.00 g, yellow oil, 84%) was prepared using a proceduresimilar to that used for the preparation of compound 181.3 usingcompound 152.1 (5.00 g) and cyclobutylmethylmagnesium bromide in placeof compound 181.2. and cyclobutylmagnesium bromide respectively.

Compound 189.2. Methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate. Toa round-bottom flask was added a solution of methyl4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.1, 8.40 g, 38.5mmol, 1.00 equiv) in AcOH (150 mL). NaIO₄ (5.00 g, 23.4 mmol, 0.50equiv), iodine (10.0 g, 39.4 mmol, 1.00 equiv), and sulfuric acid (0.3mL) were added to the reaction mixture. The resulting solution wasstirred at 60° C. for 12 h. After cooling to room temperature, thereaction was quenched with 200 mL of NaHSO₃ (aq). The mixture wasextracted with 2×200 mL of ethyl acetate, and the combined organiclayers were dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (20:1) as client to furnish 8.00 g(60%) of methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate as a whitesolid.

Compound 189.3. methyl 5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate.The title compound (5.0 g, light yellow oil, 88%) was prepared using aprocedure similar to that used for the preparation of compound 181.5using compound 189.2 (8.00 g) in place of compound 181.4.

Compound 189.4. Methyl5-carbamothioyl-4-(cyclobutylmethyl)-2-methylbenzoate. To a round-bottomflask was added a solution of methyl5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.3, 5.00 g,20.6 mmol, 1.00 equiv) in a solvent mixture of THF and H₂O (50 mL 25mL). O,O′-diethyl dithiophosphate (15.0 g, 80.5 mmol, 4.00 equip) wasadded to the reaction flask. The resulting solution was stirred at 80°C. for 48 h (CAUTION: significant gas evolution occurs—this and allother reactions described herein should be carried out in wellventilated fume hoods). After cooling to ambient temperature, thereaction was carefully quenched with 50 mL of brine. The mixture wasextracted with 3×50 mL of ethyl acetate and the combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:4) as eluent to furnish 1.20 g (21%) of thetitle compound as a yellow oil.

Compound 189.5. Methyl4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate.To a round-bottom flask was added a solution of methyl5-carbamothioyl-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.4,1.20 g, 4.33 mmol, 1.00 equiv) in tetrahydrofuran (25 mL). Iodomethane(5.00 g, 35.2 mmol, 8.00 equiv) was added to the reaction mixture. Theresulting solution was stirred at 20° C. for 12 h, and then concentratedin vacuo. This resulted in 1.10 g (87%) of methyl4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate asa yellow oil.

Compound 189.6. Methyl4-(cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate.To a round-bottom flask was added a solution of methyl4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate(compound 189.5, 1.00 g, 3.43 mmol, 1.00 equiv) in AcOH (25 mL).Propionohydrazide (1.20 g, 13.6 mmol, 4.00 equiv) was added and theresulting mixture was stirred at 100° C. for 1 h. After cooling toambient temperature, the mixture was concentrated in vacuo. The residuewas purified using silica gel column chromatography with ethylacetate/petroleum ether (1:5) as eluent to furnish 300 mg (28%) of thetitle compound as a white solid.

Compound 189.7.4-(Cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid. The title compound (260 mg, white solid, 91%) was prepared using aprocedure similar to that used for the preparation of compound 181.9using compound 189.6 (300 mg) in place of compound 181.8.

Compound 189.4-(1-(4-(Cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound (28 mg, white solid, 18%) was prepared using aprocedure similar to that used for the preparation of compound 181 usingcompound 189.7 (100 mg) in place of compound 181.9. m/z (ES+) 468(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.67 (d, 2H), 7.52-7.47 (m, 3H), 7.26(s, 1H), 3.66-3.22 (m, 1H), 3.33-3.22 (m, 1H), 3.05-2.99 (m, 4H), 2.97(q, 2H), 2.53-2.47 (m, 1H), 2.47 and 2.45 (2 singlets, amide rotamers,ArCH₃, 3H) 2.00-1.50 (m, 10H), 1.41 (t, 3H).

Compound 190.1. Methyl 2-bromo-5-iodo-4-methylbenzoate. To around-bottom flask was added a mixture of methyl2-bromo-4-methylbenzoate (2.00 g, 7.86 mmol, 1.00 equiv) in AcOH (20mL), I₂ (2.45 g, 9.65 mmol, 1.10 equiv), NaIO₄ (950 mg, 4.42 mmol, 0.50equiv), and sulfuric acid (0.1 mL, 0.15 equiv) were added and theresulting mixture was stirred at 100° C. overnight. After cooling toambient temperature, the reaction was carefully quenched with Na₂S₂O₃(aq., sat.). The resulting mixture was extracted with 2×50 mL of ethylacetate. The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo to yield 2.50 g (81%) of the title compound as anoff-white solid.

Compound 190.2. Methyl 2-bromo-5-cyano-4-methylbenzoate. The titlecompound (1.10 g, white solid, 61%) was prepared using a proceduresimilar to that used for the preparation of compound 181.5 usingcompound 190.1 (2.50 g) in place of compound 181.4.

Compound 190.3. Methyl 5-cyano-2-cyclopropyl-4-methylbenzoate. To asolution of methyl 2-bromo-5-cyano-4-methylbenzoate (compound 190.2, 600mg, 2.13 mmol, 1.00 equiv, 90%) in toluene (20 mL) under nitrogen wereadded cyclopropylboronic acid (552 mg, 6.43 mmol, 2.00 equiv), asolution of potassium carbonate (876 mg, 6.34 mmol, 2.00 equiv) in water(1 mL), Pd(dppf)Cl₂ (252 mg, 0.10 equiv), and Pd(OAc)₂ (70 mg, 0.10equiv). The resulting mixture was stirred under nitrogen at 100° C.overnight. After cooling to ambient temperature, the mixture was dilutedwith 20 mL of H₂O, then extracted with 3×50 mL of ethyl acetate. Thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo tofurnish 450 mg (89%) of methyl 5-cyano-2-cyclopropyl-4-methylbenzoate asa white solid.

Compound 190.4, Methyl 5-carbamothioyl-2-cyclopropyl-4-methylbenzoate.To a round-bottom flask, was added a solution of methyl5-cyano-2-cyclopropyl-4-methylbenzoate (compound 190.3, 220 mg, 0.920mmol, 1.00 equiv, 90%) in tetrahydrofuran (6 mL). A solution ofO,O′-diethyl dithiophosphate (300 mg, 1.61 mmol, 2.00 equiv) in water(1.5 mL) was added to the solution, and the resulting mixture wasstirred overnight at 80° C. in an oil bath (CAUTION: significant gasevolution occurs—this and all other reactions described herein should becarried out in well ventilated fume hoods). After cooling to ambienttemperature, the mixture was concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (5:1) as eluent. The collected fractions werecombined and concentrated in vacuo to furnish 100 mg (39%) of methyl5-carbamothioyl-2-cyclopropyl-4-methylbenzoate as a yellow solid.

Compound 190.5. Methyl 2-cyclopropyl-4-methyl-5-(methylsulfanyl)carboximidoylbenzoate. To a solution of methyl5-carbamothioyl-2-cyclopropyl-4-methylbenzoate (compound 190.4, 600 mg,2.17 mmol, 1.00 equiv, 90%) in THF (55 mL) was added dropwiseiodomethane (1 mL). The resulting mixture was stirred overnight at 25°C., then concentrated and dried under reduced pressure to yield 400 mg(56%) of the title compound as a yellow solid.

Compound 190.6. 2-Methoxyacetohydrazide. To a round-bottom flask, wasadded a solution of ethyl 2-methoxyacetate (10.0 g, 76.2. mmol, 1.00equiv, 90%) and NH₂NH₂.H₂O (12 mL, 3.00 equiv) in ethanol (100 mL). Theresulting solution was stirred for 3 h at 80° C. in an oil bath, thenconcentrated and dried under reduced pressure to yield 6 g (68%) of2-methoxyacetohydrazide as a white solid.

Compound 190.7. Methyl2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate.A solution of methyl2-cyclopropyl-4-methyl-5-(methylsulfanyl)carboximidoylbenzoate (compound190.5, 400 mg, 1.37 mmol, 1.00 equiv, 90%) and 2-methoxyacetohydrazide(compound 190.6, 889 mg, 7.69 mmol, 5.00 equiv) in AcOH (25 mL) wasstirred overnight at 90° C. After cooling to room temperature, themixture was concentrated in vacuo. The residue was purified using silicagel column chromatography with ethyl acetate/petroleum ether (2:1) aseluent. The collected fractions were combined and concentrated in vacuoto furnish 200 mg (44%) of methyl2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoateas a white solid.

Compound 190.8.2-Cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoicacid. To a round-bottom flask was added a solution of methyl2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate(compound 190.7, 200 mg, 0.600 mmol, 1.00 equiv, 90%) in methanol (4mL). A solution of sodium hydroxide (106 mg, 2.65 mmol, 4.00 equiv) inwater (2 mL) was added to the reaction mixture. The resulting solutionwas stirred for 2 h at 60° C. After cooling to ambient temperature, theorganic solvent was removed under reduced pressure and the pH theremaining aqueous layer was adjusted to 2-3 with hydrogen chloride (aq,6 M). The resulting solids were collected by filtration and dried toyield 170 mg (89%) of the title compound as a white solid.

Compound 190.4-(1-(2-Cyclopropyl-5-(5-methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound (115.5 mg, white solid, 51%) was prepared using aprocedure similar to that used for the preparation of compound 181 usingcompound 190.8 (150 mg) in place of compound 181.9. m/z (ES+) 456(M+H)⁺.

Compound 191.12-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoicacid. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 190.8.

Compound 191.4-(1-(2-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound (74.8 mg, white solid, 33%) was prepared using aprocedure similar to that used for the preparation of compound 181 usingcompound 191.1 (145 mg) in place of compound 181.9. m/z (ES+) 458(M+H)⁺.

Compound 192.4-(1-(2-Ethyl-4-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound191. m/z (ES+) 470 (M+H)⁺.

Compound 193.4-(1-(2-Ethyl-5-(5-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound191. m/z (ES+) 472 (M+H)⁺.

Compound 194.4-(1-(2-Ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound191. m/z (ES+) 444 (M+H)⁻.

Compound 195.4-(1-(2-Cyclobutyl-5-(5-(methoxymethyl)4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound190. m/z (ES+) 470 (M+H)⁻.

Compound 196.1. Methyl 2-isopropyl-4-methylbenzoate. To a stirredmixture of dibromozine (39.0 g, 173 mmol, 4.00 equiv) in THF (500 mL)under nitrogen at −48° C. was added dropwise isopropylmagnesium bromide(3 M in THF, 170 mmol) over a period of 30 min. Pd(dppf)Cl₂ (0.5 g, 0.05equiv) and methyl 2-bromo-4-methylbenzoate (10.0 g, 43.7 mmol, 1.00equiv) were added to the above reaction mixture. After stirring for 1 hat −48° C., the reaction mixture was quenched by the careful addition of500 mL of NH₄Cl (aq.). The resulting mixture was extracted with 3×500 mLof ethyl acetate. The combined organic layers were washed with 3×500 mLof brine and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with petroleum ether (1:1) as eluent.This resulted in 6.50 g (77%) of methyl 2-isopropyl-4-methylbenzoate asa yellow oil.

Compound 196.2. Methyl 5-iodo-2-isopropyl-4-methylbenzoate. To around-bottom flask, was added a solution of methyl2-isopropyl-4-methylbenzoate (compound 196.1, 6.50 g, 33.8 mmol, 1.00equiv) in acetic acid (60 mL). Iodide (9.50 g, 37.4 mmol, 1.10 equiv),sodium periodate (3.60 g, 16.8 mmol. 0.50 equiv), and sulfuric acid(0.500 g, 0.15 equiv) were added to the reaction mixture. The resultingsolution was stirred overnight at 100° C. After cooling to roomtemperature, the reaction was quenched with Na₂S₂O₃ (aq., sat.). Themixture extracted with 3×100 mL of ethyl acetate. The combined organiclayers were washed with 3×100 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. This resulted in 6.00 g (56%) ofmethyl 5-iodo-2-isopropyl-4-methylbenzoate as a yellow oil.

Compound 196.3. Methyl 5-cyano-2-isopropyl-4-methylbenzoate. The titlecompound (0.8 g, white solid, 37%) was prepared using a proceduresimilar to that used for the preparation of compound 181.5 usingcompound 196.2 (3.20 g) in place of compound 181.4.

Compound 196.4. Methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate. Toa round-bottom flask was added a solution of methyl5-cyano-2-isopropyl-4-methylbenzoate (compound 196.3, 800 mg, 3.68 mmol,1.00 equiv) in tetrahydrofuran/H₂O (10/5 mL). O,O′-diethyldithiophosphate (2.05 g. 11.0 mmol, 3.00 equiv) was added to thereaction mixture. The resulting solution was stirred for 15 h at 85° C.in an oil bath (CAUTION: significant gas evolution occurs—this and allother reactions described herein should be carried out in wellventilated fume hoods). After cooling to ambient temperature, themixture was extracted with 2×100 mL of ethyl acetate. The combinedorganic layers were dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:100-1:50-1:0) as eluent to furnish 0.800 g(86%) of methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate as a yellowoil.

Compound 196.5. Methyl5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate. The titlecompound (0.800 g, yellow oil, 92%) was prepared using a proceduresimilar to that used for the preparation of compound 181.7 usingcompound 196.4 (820 mg) in place of compound 181.6.

Compound 196.6. Methyl2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate.A solution of methyl5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate (compound196.5, 800 mg, 3.01 mmol, 1.00 equiv) and 2-methoxyacetohydrazide(compound 190.6, 1.90 g, 18.3 mmol, 5.00 equiv) in acetic acid (30 mL)was stirred for 2 h at 80° C. in an oil bath, then concentrated invacuo. The residue was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (1:50-1:2) as eluent to yield 250 mg(27%) of methyl2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoateas a clear oil.

Compound 196.7.2-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-(triazol-3-yl)-4-methylbenzoicacid. The tide compound (0.20 g, white solid, 84%) was prepared using aprocedure similar to that used for the preparation of compound 181.9using compound 196.6 (250 mg) in place of compound 181.8.

Compound 196.4-(1-(2-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrileand Compound 197.4-(1-(5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methyl-2-propylbenzoyl)piperidin-4-yl)benzonitrile.To a solution of2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoicacid (compound 196.7, 200 mg, 0.690 mmol, 1.00 equiv) in DMF (20 mL)were added EDCI (200 mg, 1.04 mmol, 1.51 equiv), DMAP (250 mg, 2.05mmol, 2.96 equiv), and HOBT (110 mg, 0.810 mmol, 1.18 equiv). Afterstirring for 30 min at room temperature compound 1.5, 142 mg, 0.640mmol, 0.92 equiv was added and the resulting solution was stirred for 15h at 25° C., then quenched with 100 mL of ice water. The resultingmixture was extracted with 2×200 mL of ethyl acetate. The combinedorganic layers were washed with 2×100 mL of brine, then dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:50-1:1-1:0) as eluent. The crude product(˜120 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18,19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (40.0%CH₃CN up to 55.0% in 8 min, up to 100.0% in 1 min, down to 40.0% in 1min); Detector, Waters 2489 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 57.4 mg (18%) ofcompound 196 and 11.7 mg (4%) of compound 197 as white solids. Compound196. m/z (ES+) 458 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.65-7.62 (m, 2H),7.55-7.28 (m, 4H), 4.61 (s, 2H), 3.67-3.62 (m, 1H), 3.44 (s, 3H),3.27-3.20 (m, 1H), 3.04-2.86 (m, 3H), 2.51 (s, 3H), 1.99-1.68 (m, 5H),1.31-1.26 (m, 6H). Compound 197. m/z (ES+) 458 (M+H)⁺. ¹H-NMR (300 MHz,CD₃OD): δ 7.66-7.63 (m, 2H), 7.55 (s, 7.46-7.37 (m, 2H), 7.28 (m, 1H),4.61 (s, 2H), 3.62-3.58 (m, 1H), 3.44 (s, 3H), 3.19-3.05 (m, 2H),3.04-2.91 (m, 2H), 2.73-2.45 (m, 5H), 1.98-1.54 (m, 6H), 1.05-0.85 (m,3H).

Compound 198.1. Methyl 4-isopropyl-2-methylbenzoate. A dried roundbottom flask with stir bar was purged with nitrogen and charged withdiisopropyl zinc (25 mL of a 1 M solution in THF, 25 mmol, 2.0 equiv).Methyl 4-bromo-2-methylbenzoate (compound 152.1, 2.86 g, 12.5 mmol, 1.0equiv) in 1,4-dioxane (25 mL) was added followed by addition ofPd(dppf)₂Cl₂.DCM (1.02 g, 1.25 mmol, 0.1 equiv) (exothermic uponcatalyst addition). The system was purged with additional nitrogen thenargon and heated to 100° C. for 4 hours then stirred at room temperaturefor 12 hours. The mixture was carefully quenched with 1M HCl (ag., 12mL) (some bubbling) and then diluted with water (100 mL) and ethylacetate (150 mL) and mixed. The mixture was filtered through celite andwashed with water and ethyl acetate (2×25 mL each). The layers wereseparated and the aqueous was extracted with addition ethyl acetate (50mL). The combined organics were washed with brine (50 mL), dried(Na₂SO₄), and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography (hexanes to 6% ethylacetate) to obtain the title compound as a colorless oil (2.31 g, 96%).¹H NMR (400 MHz, CDCl₃): δ 7.86 (d with fine str, J=8.8 Hz, 1 H),7.12-7.07 (m, 2H), 3.87 (s, 3H), 2.90 (septet, J=6.8 Hz, 1H), 2.59 (s,3H), 1.25 (d, J=6.8 Hz, 6H).

Compound 198.2. Methyl 5-iodo-4-isopropyl-2-methylbenzoate. To methyl4-isopropyl-2-methylbenzoate (compound 198.1, 2.31 g, 12.0 mmol, 1.0equiv) in a 100 mL round bottom flask was carefully added TFA (24 mL)and the mixture was cooled to 0° C. N-Iodosuccinimide (2.70 g, 12.0mmol, 1.0 equiv) was added portionwise over 2 minutes and the resultingmixture was added under nitrogen and stirred at 0° C. for 20 min then atroom temperature for 15 hours. The mixture was carefully diluted To amixture of dichloromethane (50 mL) and added to saturated aqueousdisodium phosphate to maintain a pH above 3 (total disodium phosphateabout 500 mL). The mixture was shaken well, separated and the aqueouswas extracted with additional DCM (5×25 mL). The combined organics waswashed with a mix of saturated sodium sulfite (10 mL) plus water (40 mL)followed by brine (50 mL), dried (Na₂SO₄), filtered and removed invacuo. The crude product was purified by silica column chromatography(hexanes to 3% ethyl acetate) to obtain the title compound as a lighttan oil (3.59 g, 94%). ¹H NMR (400 MHz, CDCl₃): δ 8.35 (s, 1H), 7.08 (s,1H), 3.87 (s, 3H), 3.17 (septet, J=6.8 Hz, 1H), 2.59 (s, 3H), 1.23 (d,J=6.8 Hz, 6H).

Compound 198.3. Methyl 5-cyano-4-isopropyl-2-methylbenzoate. To a driedround bottom flask was added methyl 5-iodo-4-isopropyl-2-methylbenzoate(compound 198.2, 2.00 g, 6.29 mmol, 1.0 equiv), zinc cyanide (1.48 g,12.6 mmol, 2.0 equiv), DMF (20 mL) and Pd(PPh₃)₄ (364 mg, 0.315 mmol,0.05 equiv). The system was purged with nitrogen followed by argon andthe mixture was heated at 100° C. for 15 hours. The reaction was allowedto cool to room temperature then diluted with ethyl acetate (50 mL) andquenched with 1 M FeSO₄ (25 mL). The mixture was stirred vigorously for40 minutes then filtered through celite and washed with 1 M FeSO₄ (15mL), water (50 mL) and ethyl acetate (150 mL). The layers were separatedand the aqueous phase was extracted with ethyl acetate (50 mL). Thecombined organic layers were washed with brine (4×100 mL), dried(Na₂SO₄), filtered, and concentrated in vacuo. The product was purifiedby silica column chromatography (hexanes to 8% ethyl acetate) to obtainthe title compound (1.14 g, 83%). ¹H NMR (400 MHz, CDCl₃): δ 8.19 (s,1H), 7.25 (s, 1H), 3.91 (s, 3H), 3.37 (septet, J=6.8 Hz, 1H), 2.67 (s,3H), 1.32 (d, J=6.8 Hz, 6H).

Compound 198.4. Methyl5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate. Methyl5-cyano-4-isopropyl-2-methylbenzoate (compound 198.3, 1.12 g, 5.16 mmol,1.0 equiv), O,O′-diethyl dithiophosphate (90%) (2.0 mL, 10.7 mmol, 2.1equiv) and water (200 μL) were added to a 16 mL vial and the mixture washeated with the cap loose at 80° C. for 85 hours (CAUTION: significantgas evolution occurs—this and all other reactions described hereinshould be carried out in well ventilated fume hoods). Note thatadditional O,O′-diethyl dithiophosphate (0.5 mL, 2.7 mmol, 0.5 equiv)and water (50 μL) was added at 6 hours and 14 hours. The intermediatethioamide is also observed by LC/MS during the reaction and is heateduntil the conversion to the desired product is complete. The reactionmixture was diluted with ethyl acetate (75 mL) and washed with saturatedaqueous NaHCO₃ (20 mL) followed by 1 M NaH₂PO₄ (10 mL) and brine (10mL). The organics were dried (Na₂SO₄), filtered and removed in vacuo.The crude product was purified by silica column chromatography (hexanesto 25% ethyl acetate) to obtain a colorless oil (1.12 g, 78%). m/z (ES+)280 (M+H)⁺.

Compound 198.5. Methyl4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate.Methyl 5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate(compound 198.4, 33 mg, 0.12 mmol, 1.0 equiv), 3-methoxypropanehydrazide(compound 143.1, 21 mg, 0.18 mmol, 1.5 equiv) and acetic acid (1.2 mL)were added to a 4-mL vial and heated at 80° C. with a loose cap for 4hours. The solvent was removed in vacuo and the residue was dissolved inDCM (10 mL) and washed with saturated NaHCO₃ (5 mL) then brine (5 mL),dried (Na₂SO₄), filtered and evaporated to a colorless oil (theoreticalyield). m/z (ES+) 318 (M+H)⁺.

Compound 198.6.4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid. To crude methyl4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate(compound 198.5, 0.12 mmol, 1.0 equiv) from the previous step in a 4-mLvial was added lithium hydroxide monohydrate (10.1 mg, 0.24 mmol, 2.0equiv) methanol (0.9 mL) and water (0.3 mL). The resulting mixture wasstirred at room temperature for 3 hours followed by 50° C. for 3 hoursand 40° C. for 17 hours. The solvents were removed in vacuo and theresidue was diluted with water (7 mL) plus saturated NaHCO₃ (1 mL) andthe aqueous was washed with diethyl ether (2 mL). The organic was backextracted with a mix of water (2 mL) plus saturated NaHCO₃ (0.5 mL). Thecombined aqueous was acidified to pH=3 with 1 M H₃PO₄ and extracted withdichlormethane (3×5 mL). The organics were dried (Na₂SO₄), filtered andremoved in vacuo to obtain the title compound as a white waxy solid(31.5 mg, 88% over 2 steps). m/z (ES+) 304 (M+H)⁺.

Compound 198.4-(1-(4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a 4-mL vial was added4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 198.6, 31 mg, 0.10 mmol, 1.0 equiv),4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 23 mg, 0.10mmol, 1.0 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (22 mg,0.13 mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (21.5 mg, 0.11 mmol, 1.1 equiv), DMF (1 mL) and DIEA (71μL, 0.41 mmol, 4 equiv). The mixture was stirred at room temperature for24 hours then diluted with ethyl acetate (10 mL) and washed with brine(10 mL). The aqueous was back extracted with ethyl acetate (3 mL) andthe combined organics was washed with saturated NaHCO₃ (5 mL), 1 MNaH₂PO₄ (5 mL), and brine (5 mL). The organics were dried (Na₂SO₄),filtered and removed in vacuo. The crude residue was purified bypreparative TLC (DCM/8% MeOH) to obtain the title compound as an offwhite solid (23 mg, 48%). m/z (ES+) 472 (M+H)⁺.

Compound 199.4-(1-(4-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 198). m/z (ES+) 458 (M+H)⁺.

Compound 200.4-(1-(4-isopropyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 198). m/z (ES+) 458 (M+H)⁺.

Compound 201.4-(1-(4-isopropyl-3-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 198). m/z (ES+) 444 (M+H)⁺.

Compound 202.1. Methyl 5-carbamoyl-4-cyclobutyl-2-methylbenzoate. To an8-mL vial was added methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (152.4,100 mg, 0.436 mmol, 1.0 equiv), potassium carbonate (181 mg, 1.31 mmol,3.0 equiv) and DMSO (2.2 mL) and stirring was initiated. Hydrogenperoxide (50 wt %) (176 μL, 3.05 mmol, 7.0 equiv) was added over about 1minute. The mixture was stirred at room temperature for 29 hours thendiluted into brine (10 mL) plus 1 M H₃PO₄ (1.5 mL). The mixture wasextracted with ethyl acetate (10 mL×1, 3 mL×1). The combined organiclayers were washed with brine (10 mL) plus a few drops of 1 M H₃PO₄followed by a mixture of water (10 mL) plus saturated NaHCO₃ (1 mL) andfinally brine (5 mL). The organics was dried (Na₂SO₄), filtered andevaporated to obtain the title compound as a white solid (59 mg, 55%).m/z (ES+) 248.0 (M+H)⁺.

Compound 202.2. Methyl4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate. To a vial wasadded methyl 5-carbamoyl-4-cyclobutyl-2-methylbenzoate (compound 202.1,59 mg, 0.24 mmol, 1.0 equiv) and N,N-dimethylformamide dimethyl acetal(1 mL) was added. The mixture was heated at 80° C. for 5 hours then thesolvents were removed in vacuo. To the residue was added acetic acid(400 μL) and a solution of anhydrous hydrazine (8.2 μL, 0.26 mmol, 1.1equiv) in acetic acid (100 μL). To the resulting thick suspension wasadded additional acetic acid (500 μL) and the mixture was stirred at 80°C. for 1.5 hours then the solvents removed in vacuo. Ethyl acetate (5mL) and DCM (5 mL) was added (some undissolved solids). The organics waswashed with saturated NaHCO₃ (10 mL) and brine (5 mL) and removed invacuo to obtain the title compound as a white solid (theoretical yield).m/z (ES+) 272 (M+H)⁺.

Compound 202.3. 4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoicacid. To crude methyl4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate (compound 202.2,0.24 mmol, 1.0 equiv) from the previous step in a 4-mL vial was addedmethanol (1.5 mL) and water (0.5 mL) and lithium hydroxide monohydrate(20 mg, 0.48 mmol, 2.0 equiv). The resulting mixture was stirred at 40°C. for 42 hours. The reaction mixture was diluted into water (5 mL),acidified to pH 3 with 1M H₃PO₄ and extracted with DCM (3×5 mL). Theorganics were dried (Na₂SO₄), filtered and concentrated in vacuo toobtain the title compound as a white solid (61 mg, 98% over 2 steps).m/z (ES+) 258 (M+H)⁺.

Compound 202.4-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.To a 4-mL vial was added4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound202.3, 31 mg, 0.12 mmol, 1.0 equiv), 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 27 mg, 0.12 mmol, 1.0 equiv),1-hydroxybenzotriazole hydrate (20 wt % water) (25 mg, 0.15 mmol, 1.25equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (25mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83 μL, 0.48 mmol, 4equiv). The mixture was stirred at room temperature for 4 hours thendiluted with ethyl acetate (10 mL) and washed with 1 M NaH₂PO₄ (5 mL).The aqueous was back extracted with ethyl acetate (3 mL) and thecombined organics was washed with brine (5 mL), saturated NaHCO₃ (5 mL)and brine (5 mL). The organics were dried (Na₂SO₄), filtered and removedin vacuo. The crude residue was purified by preparative TLC (DCM/8%MeOH) to obtain the title compound as a white solid (23 mg, 46%). m/z(ES+) 426 (M+H)⁺.

Compound 203.4-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.To a 4-mL vial was added4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound202.3, 31 mg, 0.12 mmol, 1.0 equiv),4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 31 mg, 0.13 mmol,1.1 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (25 mg, 0.15mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (25 mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83μL, 0.48 mmol, 4 equiv). The mixture was stirred at room temperature for4 hours then diluted with ethyl acetate (10 mL) and washed with 1 MNaH₂PO₄ (5 mL). The aqueous was back extracted with ethyl acetate (3 mL)and the combined organics was washed with brine (5 mL), saturated NaHCO₃(5 mL) and brine (5 mL). The organics were dried (Na₂SO₄), filtered andremoved in vacuo. The crude residue was purified by preparative TLC(DCM/8% MeOH) to obtain the title compound as a white solid (30 mg,56%). m/z (ES+) 444 (M+H)⁻.

Compound 204.1. Methyl 2,4-dibromobenzoate. A solution of2,4-dibromobenzoic acid (52.0 g, 176 mmol, 1.00 equiv, 95%) and sulfuricacid (20 mL) in methanol (400 mL) was stirred at 90° C. overnight. Aftercooling to room temperature, the mixture was concentrated under reducedpressure. The residue was diluted with 500 mL of ethyl acetate andwashed with 3×100 mL of H₂O followed by 1×100 mL of NaHCO₃ (aq., sat.Note: gas evolution occurs). The organic layer was dried over anhydroussodium sulfate and concentrated in vacuo. This resulted in 45.0 g (78%)of methyl 2,4-dibromobenzoate as a yellow oil.

Compound 204.2. Methyl 2,4-diethylbenzoate. To stirred mixture of ZnBr₂(40.0 g, 176 mmol, 5.44 equiv, 99%) in THF (100 mL) under nitrogen at 0°C. was added dropwise EtMgBr (60 mL, 3 M in THF). After 0.5 h at 0° C.,the temperature was lowered to −78° C. and PdCl₂(dppf) (3.72 g, 5.03mmol, 0.16 equiv, 99%) was added followed by the dropwise addition of asolution of methyl 2,4-dibromobenzoate (compound 204.1, 10.0 g, 32.3mmol, 1.00 equiv, 95%) in THF (200 mL). The reaction was stirredovernight at room temperature, then carefully quenched with waterfollowed by HCl (aq., 1 M). The resulting mixture was extracted with3×500 mL of ethyl acetate, and the combined organic layers were washedwith 3×50 mL of brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:60) as eluent tofurnish 6.30 g (96%) of methyl 2,4-diethylbenzoate as a colorless oil

Compound 204.3. Methyl 2,4-diethyl-5-iodobenzoate. The title compound(4.0 g, light yellow oil, 69%) was prepared using a procedure similar tothat used for the preparation of compound 181.4 using compound 204.2(3.50 g) in place of compound 181.3.

Compound 204.4. 2,4-Diethyl-5-iodobenzoic acid. The title compound (3.24g, white solid, 85%) was prepared using a procedure similar to that usedfor the preparation of compound 181.9 using compound 204.3 (4.00 g) inplace of compound 181.8.

Compound 204.5. 2,4-Diethyl-5-(methoxycarbonyl)benzoic acid. To astirred solution of 2,4-diethyl-5-iodobenzoic acid (compound 204.4, 500mg, 1.64 mmol, 1.00 equiv, 90%) in tetrahydrofuran (20 mL) at −78° C.under nitrogen was added dropwise a solution of n-BuLi (1.73 mL, 4.10mmol, 2.36 M in THF). After 5 minutes, a solution of methylchloroformate (0.315 mL, 4.10 mmol, 2.50 equiv) in THF (5 mL) was addeddropwise to the reaction at −78° C. over 5 minutes. The reaction wasstirred for another 5 min at −78° C., and then carefully quenched with10 mL of water. The pH was adjusted to 1-2 with hydrochloric acid (6 M)and the resulting mixture was extracted with ethyl acetate (2×30 mL).The combined organic layers were washed with 20 mL of brine, then driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by silica gel column chromatograph with ethylacetate-petroleum ether (1:20) as eluent to yield 96 mg (25%) of thetitle compound as an off-white solid.

Compound 204.6. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-diethylbenzoate. To around-bottom flask, were added a solution of2,4-diethyl-5-(methoxycarbonyl)benzoic acid (compound 204.5, 500 mg,2.12 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.5, 470 mg, 2.12. mmol, 1 equiv), EDC.HCl (810 mg, 4.24 mmol,2.00 equiv), and 4-dimethylaminopyridine (520 mg, 4.24 mmol, 2 equiv) inN,N-dimethylformamide (15 mL). The reaction was stirred overnight at 25°C. Upon reaction completion, the reaction mixture was diluted with 30 mLof ethyl acetate, then washed with 1×20 mL of NH₄Cl (aq.) and 1×20 mL ofbrine. The organic phase was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica gelchromatography with a solvent mixture of ethyl acetate and petroleumether (1:1) to yield 500 mg (60%) of the title compound as a pale yellowsolid.

Compound 204.7.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide. Toa solution of compound 204.6 (500 mg, 1.05 mmol, 1.00 equiv, 85%) inethanol (6 mL) was added hydrazine hydrate (3 mL). The resultingsolution was stirred overnight at 90° C. After cooling to ambienttemperature, the mixture was concentrated in vacuo. The residue wasdiluted with 20 mL of ethyl acetate, then washed with 1×5 mL of brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography withdichloromethane-methanol (20:1) as eluent to yield 260 mg (55%) of thedesired compound as a yellow solid.

Compound 204.8.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide(compound 204.7, 100 mg, 0.220 mmol, 1.00 equiv, 90%) in a solventmixture of water (2 mL) and dioxane (3 mL). Sodium bicarbonate (62 mg,0.740 mmol, 3.00 equiv) was added to the reaction mixture at roomtemperature, and stirred for 5 minutes. BrCN (75 mg, 0.740 mmol, 3.00equiv) was then added to the reaction at room temperature. The resultingsolution was stirred for 2 h at room temperature, then quenched with 30mL of FeSO₄ aq., sat.) and diluted with ethyl acetate. The resultingmixture was stirred vigorously then filtered through celite and washedwith 1 M FeSO₄, water, and ethyl acetate. The layers were separated andthe aqueous phase was extracted with 2×50 mL of ethyl acetate. Thecombined organic layers were washed with 2×50 mL of brine, dried overanhydrous sodium sulfate, and concentrated in vacuo. This resulted in100 mg (89%) of the title compound as a yellow solid. The compound wasused in the next step reaction without further purification.

Compound 204.9.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzamide.A mixture of compound 204.8 (100 mg, 0.200 mmol, 1.00 equiv, 85%) andpotassium hydroxide (132 mg, 2.35 mmol, 10.0 equiv) in ethanol (10 mL)was stirred at 85° C. overnight. After cooling to ambient temperature,the pH was adjusted to 7 with acetic acid and the resulting solution wasconcentrated in vacuo. The residue was diluted with 50 mL of ethylacetate, washed with 2×20 mL of brine, then concentrated in vacuo. Thecrude product was dried in a vacuum oven, before it was charged onto asilica gel column, and purified with dichloromethane-methanol (20:1) toafford 100 mg (85%) of the title compound as a yellow solid.

Compound 204.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzamide(compound 204.9, 100 mg, 0.170 mmol, 1.00 equiv) in dichloromethane (10mL). Triethylamine (170 mg, 1.68 mmol, 8.00 equiv) was added to thereaction at room temperature, followed by dropwise addition of asolution of (CF₃CO)₂O (160 mg, 0.760 mmol, 4.50 equiv) indichloromethane (0.5 mL) at 0 to 5° C. The resulting solution wasstirred at room temperature for another 2 hours. The mixture was dilutedwith 60 mL of ethyl acetate, then washed with 3×20 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate, and concentratedin vacuo. The residue was purified by prep-HPLC (SunFire Prep C18,19*150 mm 5 um, water with 0.05% TFA and CH₃CN (53.0% CH₃CN up to 65.0%in 8 min, up to 100.0% in 2 min, down to 53.0% in 1 min). The fractionscontaining pure compound were combined and lyophilized to yield 50 mg(50%) of the title compound as a white solid. nil z (ES+) 458 (M+H)⁺. ¹HNMR (300 MHz, CD₃OD): δ 7.63 (d, 2H), 7.45-7.30 (m, 4H), 4.89-4.80 (m,1H, overlapped), 4.36 (q, 2H), 3.60-3.57 (m, 1H), 3.29-3.23 (m, 1H),3.19-2.85 (m, 4H), 2.74-2.56 (m, 2H), 2.00-1.82 (m, 1H), 1.77-1.66 (m,3H), 1.40 (t, 3H), 1.30-1.21 (m, 3H), 1.11 (t, 3H).

Compound 205.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204). m/z (ES+) 430 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69(d, 2H), 7.52-7.47 (m, 3H), 7.29 (s, 1H), 4.89-4.80 (m, 1H, overlapped).4.42-4.40 (m, 2H), 3.64-3.61 (m, 1H), 3.02-2.96 (m, 2H), 2.51 (s, 3H),2.41 and 2.31 (2 singlets, amide rotamers, ArCH₃, 3H), 2.05-2.02 (m,1H), 1.77-1.46 (m, 3H), 1.45 (t, 3H).

Compound 206.4-(1-(5-(5-(2-Methoxyethoxy)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204). m/z (ES+) 460 (M+H)⁺.

Compound 207.4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)oxy)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204). m/z (ES+) 472 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69(d, J=6.0 Hz, 2H), 7.58-7.37 (m, 3H), 7.30 (br s, 1H), 5.40 (br s, 1H),˜4.9 (1H partially obscured by water peak), 4.08-3.96 (m, 3H), 3.96-3.88(m, 1H), 3.71-3.58 (m, 1H), 3.33-3.22 (m, 1H), 3.00 (t with finestructure, J=9.0 Hz, 2H), 2.52 (s, 3H), 2.42 & 2.32 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.38-2.20 (m, 2H), 2.08-1.97 (m, 1H), 1.93-1.55(m, 3H).

Compound 208.4-(1-(2,4-Diethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204.8, 80.0 mg, 0,150 mmol, 1.00 equiv, 80%) and potassiumhydroxide (104 mg, 1.85 mmol, 10.00 equiv) in methanol (10 mL). Theresulting mixture was stirred at room temperature overnight, thenconcentrated in vacuo. The residue was purified using silica gel columnchromatography with dichloromethane/methanol (20:1) as eluent. The crudeproduct (50 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18,19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (40% CH₃CNup to 64% in 8 min, up to 100% in 1 min, down to 40% in 1 min);Detector, Waters 2489 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 1.7 mg (3%) of the titlecompound as a white solid. m/z (ES+) 444 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.63 (d, J=5.7 Hz, 2H), 7.45-7.30 (m, 4H), 4.85-4.80 (m, 1H),4.02 (s, 3H), 3.65-3.62 (m, 1H), 3.15-3.10 (m, 1H), 2.90-2.84 (m, 4H),2.72-2.60 (m, 2H), 2.02-2.00 (m, 1H), 1.72-1.65 (m, 3H), 1.30-1.25 (m,3H), 1.11 (t, 3H).

Compound 209.1.2,4-Diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound198.6), but using methyl 2,4-diethyl-5-iodobenzoate (compound 204.3)instead compound 198.2 as the starting material.

Compound 209.4-(1-(2,4-Diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid(compound 209.1, 300 mg, 0.940 mmol, 1.00 equiv, 95%) inN,N-dimethylformamide (20 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 243 mg, 1.09 mmol, 1.10 equiv), EDC.HCl(380 mg, 1.98 mmol, 2.00 equiv), and 4-dimethylaminopyridine (240 mg,1.96 mmol, 2.09 equiv) were added to the reaction mixture. The resultingsolution was stirred overnight at room temperature, then diluted with100 mL of ethyl acetate. The organic layer was washed with 3×15 mL ofbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified using silica gel column chromatography withethyl acetate as eluent. The crude product (300 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (35% CH₃CN up to 60% in 8 min, up to 100% in 1 min, downto 35% in 1 min); Detector, Waters 2489 254 & 220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 188 mg(42%) of the title compound as a white solid. m/z (ES+) 472 (M+H)⁺.

Compound 210.4-(1-(2,4-Diethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 209) but using tetrahydrofuran-3-carbohydrazide (compound38.2) instead of 3-methoxypropanehydrazide (compound 143.1). m/z (ES+)484.05 (M+H)⁺.

Compound 211.2, Methyl 2-ethyl-5-iodo-4-methylbenzoate. To around-bottom flask was added a solution of methyl2-ethyl-4-methylbenzoate (compound 48.1, 12.5 g, 70.1 mmol, 1.00 equiv)in AcOH (100 mL). NaIO₄ (7.51 g, 35.1 mmol, 0.50 equiv) and I₂ (21.4 g,84.3 mmol, 1.20 equiv) were added in portions at 25° C. Sulfuric acid(1.60 g, 16.3 mmol, 0.20 equiv) was then added to the reaction mixturedropwise at 25° C. The resulting solution was stirred for 12 h at 110°C. in an oil bath, and then cooled to ambient temperature. The reactionwas quenched with 150 mL of Na₂S₂O₃ (aq., sat.). The aqueous phase wasextracted with 2×200 mL of ethyl acetate. The combined organic layerswere washed with 3×300 mL of sodium bicarbonate (aq.) and 1×150 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated in vacuo This resulted in 20.0 g (94%) of methyl2-ethyl-5-iodo-4-methylbenzoate as a yellow oil.

Compound 211.3. 2-Ethyl-5-iodo-4-methylbenzoic acid. To a round-bottomflask, was added a solution of methyl 2-ethyl-5-iodo-4-methylbenzoate(compound 211.2, 10.0 g, 32.9 mmol, 1.00 equiv) in methanol (40 mL). Asolution of NaOH (5.26 g. 132 mmol, 4.00 equiv) in water (20 mL) wasadded dropwise. After stirring for 12 h at 40° C., the organic solventwas removed under reduced pressure. The pH of the remaining aqueousphase was adjusted to 4 with hydrogen chloride (aq., 6 M), thenextracted with 2×100 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo. Thisresulted in 9.30 g (97%) of 2-ethyl-5-iodo-4-methylbenzoic acid as awhite solid.

Compound 211.4. 2-Ethyl-5-formyl-4-methylbenzoic acid. To a stirredsolution of 2-ethyl-5-iodo-4-methylbenzoic acid (compound 211.3, 5.00 g.17.2 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) at −78° C. undernitrogen was added dropwise n-BuLi (17 mL, 2 M in THF, 2.00 equiv).After 1 h at −78° C., DMF (7.00 g, 95.8 mmol, 3.00 equiv) was addeddropwise at −78° C. The resulting solution was slowly warmed up to 25°C., then carefully quenched with water followed by the addition of 10 mLof HCl (aq., 6 M). The aqueous phase was extracted with 3×100 mL ofethyl acetate. The combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(2:1) as eluent to furnish 450 mg (14%) of2-ethyl-5-formyl-4-methylbenzoic acid as a yellow solid.

Compound 211.5. 4-(1-(2-Ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile. To a round-bottom flaskwas added a solution of 2-ethyl-5-formyl-4-methylbenzoic acid (compound211.4, 450 mg, 2.34 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL).DIEA (907 mg, 7.02 mmol, 3.00 equiv) and HBTU (1.30 g, 3.43 mmol, 1.50equiv) were added to the reaction mixture. The resulting solution wasstirred for 30 min at 25° C. A solution of4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 624 mg, 2.80mmol, 1.20 equiv) in DIEA (2 mL) was added dropwise. The resultingsolution was stirred for 30 min at 25° C., then quenched with 20 mL ofwater. The aqueous phase was extracted with 3×30 mL of ethyl acetate.The combined organic layers were washed with 1×50 mL of brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (5:1) as eluent to furnish 720 mg (85%) of thetitle compound as a yellow solid.

Compound 211.6.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic5acid. To a round-bottom flask was added a solution of4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 211.5, 720 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran (20mL). A solution of KMnO₄ (640 mg, 4.05 mmol, 2.00 equiv) in water (20mL) was added dropwise. The resulting solution was stirred for 15 h at60° C. then cooled to rt with a water bath. The solids were removed withfiltration. The filtrate was extracted with 3×30 mL of ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. This resulted in 600 mg (80%) of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acidas a light yellow solid.

Compound 211.7. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate. Toa round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acid(compound 211.6, 600 mg, 1.59 mmol, 1.00 equiv) in methanol (30 mL). Tothis was added sulfuric acid (500 mg, 5.10 mmol, 3.20 equiv) dropwise.The resulting solution was stirred for 15 h at 60° C. After cooling toambient temperature, the mixture was concentrated in vacuo. The residuewas diluted with 20 mL of H₂O. The aqueous phase was extracted with 3×20mL of ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfite and concentrated in vacuo. This resulted in 500mg (80%) of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate as ayellow oil.

Compound 211.8.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide.To a round-bottom flask was added a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate(compound 211.7, 500 mg, 1.28 mmol, 1.00 equiv) in ethanol (20 mL).Hydrazine (4 mL) was added to the reaction mixture. The resultingsolution was stirred for 15 h at 80° C., then concentrated in vacuo. Theresidue was partitioned between water and ethyl acetate. The aquoeueslayer was extracted with ethyl acetate (2×). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo toyield 400 mg (80%) of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazideas a light yellow solid.

Compound 211.9. N-(Morpholine-4-carbonothioyl)benzamide. To a 50-mLthree neck round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was added a solution of morpholine (1.00g, 11.5 mmol, 1.00 equiv) in acetone (10 mL). TEA (1.74 g. 17.2 mmol,1.50 equiv) was added to the reaction, and the resulting solution wasstirred for 30 min at 25° C. Benzoyl isothiocyanate (1.87 g, 11.5 mmol,2.00 equiv) was added dropwise to the reaction at 0° C. The resultingsolution was stirred for 30 min at 0° C., then quenched with 20 mL ofwater. The mixture was extracted with 2×30 mL of ethyl acetate. Thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:10-1:3) as eluent to furnish 2.30 g(80%) of N-(morpholine-4-carbonothioyl)benzamide as a yellow solid.

Compound 211.10. Morpholine-4-carbothioamide. To a round-bottom flaskwas added a solution of N-(morpholine-4-carbonothioyl)benzamide(compound 211.9, 3.00 g, 12.0 mmol, 1.00 equiv) in methanol (20 mL). Asolution of sodium hydroxide (1.44 g, 36.0 mmol, 3.00 equiv) in water(20 mL) was added to the reaction. The resulting solution was stirredovernight at 60° C. After cooling to ambient temperature, the organicsolvent was removed under reduced pressure. The residue was extractedwith 2×20 mL of ethyl acetate/petroleum ether(1:1). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated invacuo. This resulted in 430 mg (25%) of morpholine-4-carbothioamide as ayellow solid.

Compound 211.11. 4-(Methylsulfanyl)carboximidoylmorpholine. A solutionof morpholine-4-carbothioamide (compound 211.10, 430 mg, 2.94 mmol, 1.00equiv; and iodomethane (1.25 g, 8.81 mmol, 3.00 equiv) intetrahydrofuran (10 mL) was stirred for 4 h at 25° C., then concentratedin vacuo. This resulted in 471 mg (100%) of4-(methylsulfanyl)carboximidoylmorpholine as a yellow solid.

Compound 211.4-(1-(2-Ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.To a 20-mL sealed tube was added solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide(compound 211.8, 225 mg, 0.580 mmol, 1.00 equiv) in pyridine (10 mL).4-(Methylsulfanyl) carboximidoylmorpholine (compound 211.11, 200 mg,1.25 mmol, 1.00 equiv) was added to the reaction mixture. The resultingsolution was stirred for 3 days at 100° C. behind a blast shield. Aftercooling to room temperature, the mixture was then concentrated in vacuo.The residue was purified using silica gel column chromatography withchloroform/methanol (30:1) as eluent. The crude product (˜100 mg) waspurified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase,water with 0.03% NH₃H₂O and CH₃CN (32% CH₃CN up to 55% in 8 min, up to100% in 2 min, down to 32% in 1 min); Detector, Waters 2489 254 & 220nm. The fractions containing pure compound were combined and lyophilizedto yield 67.7 mg (24%) of the title compound as a white solid. m/z (ES+)485 (M+H)⁻. ¹H-NMR (300 MHz, CD₃OD): δ 7.69 (d, 2H), 7.49-7.31 (m, 4H),4.90-4.80 (m, 1H), 3.83-3.81 (m, 4H), 3.79-3.65 (m, 1H), 3.60-3.41 (m,4H), 3.40-3.31 (m, 1H), 3.08-2.97 (m, 2H), 2.76-2.71 (m, 2H), 2.51 (s,3H), 2.02-1.98 (m, 1H), 1.85-1.80 (m, 3H), 1.33-1.30 (m, 3H).

Compound 212.4-(1-(5-(5-((2-Methoxyethyl)(methyl)amino)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 211). m/z (ES+) 473 (M+H)⁺.

Compound 213.4-(1-(2,4-Dimethyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 211). m/z (ES+) 471 (M+H)⁺.

Compound 214.4-(1-(2,4-Dimethyl-5-(5-(pyrrolidin-1-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 211). m/z (ES+) 455 (M+H)⁺.

Compound 215.3. 4-Cyclobutyl-2-ethyl-5-iodobenzoic acid. To around-bottom flask, was added a solution of methyl4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 10.3 g, 30.0 mmol,1.00 equiv) in methanol (100 mL). A solution of sodium hydroxide (3.60g, 3.00 equiv) in water (10 mL) was added dropwise to the stirredreaction mixture. The resulting mixture was stirred for 2 h at 60° C.After cooling to ambient temperature, the volatiles were removed underreduced pressure. The pH of the remaining aqueous mixture was adjustedto ˜4 using HCl (aq., 1 M). The resulting precipitate was collected byfiltration and dried to yield 9.00 g (91%) of4-cyclobutyl-2-ethyl-5-iodobenzoic acid as a white solid.

Compound 215.4. 4-Cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid. Toa solution of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid (compound 215.3,3.30 g, 10.0 mmol, 1.00 equiv) in THF (40 mL) was added n-BuLi (2.5 M,9.50 mL, 2.38 equiv) dropwise at −78° C. under nitrogen atmosphere. Theresulting solution was stirred for another 20 min at the sametemperature, followed by the addition of a solution of dimethylcarbonate (2.70 g, 30.0 mmol, 3.00 equiv) in tetrahydrofuran (2 mL)dropwise. The reaction temperature was slowly raised to 25° C. andstirred for another 1 h, then slowly quenched with 50 mL of water. ThepH was adjusted to ˜4 with HCl (aq., 1 M) and the resulting mixture wasextracted with 100 mL of ethyl acetate. The combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:3) as client to furnish 1.80 g (69%) of thedesired product as a white solid.

Compound 215.5. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate.To a round-bottom flask were added a solution of4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4,1.15 g, 4.38 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.10 equiv), HBTU (2.50g, 659 mmol, 1.50 equiv), and DIEA (1.07 g, 8.28 mmol, 3.00 equiv) inN,N-dimethylformamide (10 mL). The resulting solution was stirred for 1h at 25° C. The reaction was then quenched by the addition of 20 mL ofwater. The resulting mixture was extracted with 2×50 mL of ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography with ethyl acetate/petroleum ether (1:3) toyield 1.80 g (95%) of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoateas a yellow solid.

Compound 215.6.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide.To a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate(compound 215.5, 2.15 g, 4.99 mmol, 1.00 equiv) in methanol (20 mL), wasadded hydrazine hydrate (80%, 15 mL) batchwise. The reaction was stirredat 80° C. overnight. After cooling to ambient temperature, the mixturewas concentrated under reduced pressure. The residue was extracted withdichloromethane (2×100 mL). The combined organic layers were dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue waspurified by silica gel chromatography with dichloromethane/methanol(100:1) to furnish 1.13 g (53%) of the desired product as a pinkishsolid.

Compound 215.7.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile.To a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide(compound 215.6, 600 mg, 1.39 mmol, 1.00 equiv) in 1,4-dioxane (10 mL)was added 10 mL of an aqueous solution of sodium bicarbonate (350 mg,4.17 mmol, 1.00 equiv). Cyanogen bromide (220 mg, 2.08 mmol, 1.50 equiv)was added to the reaction mixture dropwise. The reaction mixture wasstirred at 25° C. for 2 h, then quenched with 20 mL of FeSO₄ (aq., sat.)and diluted with DCM. The resulting mixture was stirred vigorously thenfiltered through celite and washed with 1 MFeSO₄, water, and ethylacetate. The layers were separated and the aqueous phase was extractedwith 2×50 of DCM. The combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo. This resulted in 600 mg (95%)of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrileas an off-white solid.

Compound 215.8.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide.To a 10-mL sealed tube, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile(compound 215.7, 228 mg, 0.500 mmol, 1.00 equiv) in ethanol (5 mL). Thiswas followed by the addition of potassium hydroxide (280 mg, 4.99 mmol,10.0 equiv) in portions. The resulting solution was stirred for 5 h at80° C. behind a blast shield. After cooling to ambient temperature, thereaction was then quenched by the addition of 15 of water and extractedwith 2×20 mL of ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated in vacuo. This resultedin 200 mg (80%) of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamideas a yellow solid.

Compound 215.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of compound 215.8 (251 mg,0.500 mmol, 1.00 equiv) in dichloromethane (5 This was followed by theaddition of (CF₃CO)₂O (158 mg, 1.50 equiv) dropwise with stirring.Triethylamine (101 mg, 1.00 mmol, 2.00 equiv) was added dropwise withstirring. The resulting mixture was stirred at 25° C. for 1 h, thenconcentrated in vacuo. The residue was purified using silica gel columnchromatography with dichloromethane/methanol (20:1) as eluent. The crudeproduct (120 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (54.0% CH₃CN up to 64.0% in6 min, up to 100.0% in 1 min, down to 54.0% in 1 min); Detector, Waters2489 254 & 220 nm. The fractions containing pure compound were combinedand lyophilized to yield 60 mg (25%) of the title compound as a whitesolid. m/z (ES+) 484 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.64 (d, 2H),7.45-7.21 (m, 4H), 4.37 (q, 2H), 4.02-3.96 (m, 1H), 3.60-3.53 (m, 1H),3.29-3.19 (m, 2H), 2.98-2.90 (m, 2H), 2.76-2.61 (m, 2H), 2.15-2.12 (m,2H), 2.07-1.92 (m, 4H), 1.80-1.68 (m, 4H), 1.35 (t, 3H), 1.29-1.20 (m,3H).

Compound 216.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile(compound 215). m/z (ES+) 470 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.64(d, 2H), 7.45-7.38 (m, 3H), 7.32 and 7.21 (2 singlets, amide rotamers,1H), 4.0 (s, 3H), 4.00-3.95 (m, 1H), 3.63-3.56 (m, 1H), 3.29-3.19 (m,2H), 298 (app t, 2H), 2.76-2.61 (m, 2H), 2.17-1.89 (m, 6H), 1.80-1.64(m, 4H), 1.32-1.20 (m, 3H).

Compound 217.1. Methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate.To a round-bottom flask was added a solution of4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4,70.0 mg, 0.270 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). HBTU(210 mg, 0.550 mmol, 2.07 equiv), DIEA (150 mg, 1.16 mmol, 4.35 equiv)were added to the reaction mixture at 0° C., and stirred for 30 min.This was followed by the addition of4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 HClsalt, 80.0 mg, 0.330 mmol, 1.20 equiv). The resulting solution wasstirred for 15 h at 25° C., and then quenched with 20 mL of ice-water.The mixture was extracted with 2×50 mL of ethyl acetate. The combinedorganic layers were washed with 1×50 mL of brine, dried over anhydroussodium sulfate, and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography with ethyl acetate/petroleumether (1:100-1:5) as eluent to yield 100 mg (84%) of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoateas a white solid.

Compound 217.2.5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide.To a round-bottom flask was added a solution of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate(compound 217.1, 1.10 g, 2.45 mmol, 1.00 equiv) in ethanol (40 mL).Hydrazine hydrate (20 mL) was added to the reaction mixture, and thereaction was stirred 80° C. for 15 h. After cooling to ambienttemperature, the mixture was concentrated in vacuo, then diluted with 50mL of H₂O. The resulting mixture was extracted with 3×50 mL ofdichloromethane. The combined organic layers were washed with 2×50 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated in vacuo.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:1-1:0) as eluent to yield 900 mg (82%)of5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazideas a white solid.

Compound 217.3.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide(compound 217.2, 450 mg, 1.00 mmol, 1.00 equiv) in 1,4-dioxane (10 mL).A solution of sodium bicarbonate (252 mg, 3.00 mmol, 2.99 equiv) inwater (10 mL) and BrCN (128 mg, 1.21 mmol, 1.20 equiv) were added to thereaction mixture. The resulting solution was stirred for 3 h at roomtemperature, then quenched with 30 mL of FeSO₄ (aq., sat.) and dilutedwith ethyl acetate. The resulting mixture was stirred vigorously thenfiltered through celite and washed with 1 M FeSO₄, water, and ethylacetate. The layers were separated and the aqueous phase was extractedwith 2×50 mL of ethyl acetate. The combined organic layers were washedwith 2×50 mL of brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. This resulted in 400 mg (84%) of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrileas a light brown solid.

Compound 217.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 217.3, 200 mg, 0.420 mmol, 1.00 equiv) in methanol (20 mL).Potassium hydroxide (237 mg, 4.22. mmol, 10.0 equiv) was added to thereaction mixture. The resulting solution was stirred for 15 h at 70° C.After cooling to ambient temperature, the organic solvent was removedunder reduced pressure. The residue was diluted with 30 mL of H₂O, thenextracted with 2×50 mL of ethyl acetate. The combined organic layerswere washed with 2×50 mL of brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product (50 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (49.0% CH₃CN up to 63.0% in 8 min, up to 100.0% in 1 min,down to 49.0% in 1 min); Detector, Waters 2489 254 & 220 nm. Thefractions containing pure compound were combined and lyophilized toyield 20 mg (10%) of the title compound as a white. m/z (ES+) 488(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.72 (d, 2H), 7.64-7.61 (m, 2H),7.39-7.25 (m, 2H), 4.85-4.78 (m, 1H), 4.00-3.93 (m, 4H), 3.54-3.49 (m,2H), 3.28-3.22 (m, 1H), 2.80-2.65 (m, 2H), 2.26-1.84 (m, 10H), 1.45-1.27(m, 3H).

Compound 218.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile(compound 215) and using compound 11.2 HCl salt in place of compound1.5. m/z (ES+) 502 [M+H]⁺, 543 [M+CH₃CN+H]⁺. ¹H-NMR (300 MHz, CD₃OD): δ7.73 (d, 2H), 7.64-7.58 (m, 2H), 7.39-7.26 (m, 2H), 489-4.82 (m, 1H),4.35 (q, 2H), 4.10-3.95 (m, 1H), 3.50-3.38 (m, 2H), 3.30-3.27 (m, 1H),2.75-2.65 (m, 2H), 2.22-1.86 (m, 10H), 1.41 (t, 3H), 1.35-1.20 (m, 3H).

Compound 219.1 Methyl 2-bromo-4-methylbenzoate. To a solution of2-bromo-4-methylbenzoic acid (10 g) in MeOH (50 ml) was added dropwiseconcentrated sulfuric acid (10 ml) at 0° C. The mixture was heated at70° C. for 2 hours. After cooling to ambient temperature, the methanolwas removed under reduced pressure. The residue was poured intoice-water (100 ml). The mixture was extracted with EtOAc (×2). Thecombined organic layers were washed with NaHCO₃ (aq. sat. Note: gasevolution), brine, dried over MgSO₄, filtered, and concentrated to givethe product as a clear oil. Yield: 10.5 g, 99%. ¹H NMR (400 MHz,Chloroform-d) δ 7.73 (d, 1H), 7.50 (d, 1H), 7.19-7.11 (m, 1H), 3.92 (s,3H), 2.36 (s, 3H).

Compound 219.2 Methyl 2-cyclobutyl-4-methylbenzoate. Cyclobutylzinc(II)bromide (50 ml, 0.5M in THF, 25.0 mmol) was added to a mixture of methyl2-bromo-4-methylbenzoate (219.1, 5.0 g, 21.8 mmol) and PdCl₂(dppf)CH₂Cl₂(1.78 g, 2.20 mmol). The mixture was degassed and the flask was filledwith argon through a balloon. After the mixture was heated at 65° C.under argon for 24 hours, it was cooled to 0° C. and quenched with water(10 ml). The mixture was diluted with EtOAc (200 ml), washed with waterthen with brine. The EtOAc layer was dried (Na₂SO₄), concentrated, andpurified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to20:1). Yield: 3.6 g, 81%. ¹H NMR (400 MHz, Chloroform-d) δ 7.68 (d, 1H),7.23-7.17 (s, 1H), 7.03 (d, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 2.39 (s,3H), 2.34 (m, 2H), 2.16-1.96 (m, 3H), 1.80 (m, 1H).

Compound 219.3 Methyl 2-cyclobutyl-5-iodo-4-methylbenzoate.N-Iodosuccinimide (5.25 g, 23.3 mmol) was added portionwise to asolution of methyl 2-cyclobutyl-4-methylbenzoate (219.2, 4.77 g, 23.3mmol) in concentrated sulfuric acid (100 ml) at 0° C. The mixture turnedvery thick after it was stirred at 0° C. for 30 min and at RT for 2hours. The mixture was cooled to 0° C. again and MeOH (100 ml) wasadded. The mixture was heated at 60° C. for 2 hours. The methanol wasremoved under reduced pressure and the residue was poured into ice water(200 ml). The mixture was extracted with EtOAc (2×). The combinedorganic layers were washed with brine, then aq. 1N NaHCO₃, dried(Na₂SO₄), and concentrated. The residue was purified using column(silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 5.0 g,clear oil, 65%. ¹H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.24 (s,1H), 4.17-4.04 (m, 1H), 3.86 (s, 3H), 2.48-2.44 (s, 3H), 2.40-2.28 (m,2H), 2.13-1.92 (m, 3H), 1.85-1.75 (m, 1H).

Compound 219.4 Methyl 5-cyano-2-cyclobutyl-4-methylbenzoate. A mixtureof methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (219.3, 3.0 g, 9.1 mmol),Zn(CN)₂ (2.3 g, 19.6 mmol) and Pd(PPh₃)₄ (0.55 g, 0.47 mmol) in DMF (50ml) was degassed and the flask was filled with argon through a balloon.The mixture was heated at 100° C. under argon overnight. After coolingto ambient temperature, the reaction was quenched with saturated aq.FeSO₄ (20 ml) and diluted with EtOAc (200 ml). The mixture was stirredvigorously then filtered through celite and washed with 1 M FeSO₄, waterand ethyl acetate. The layers were separated and the aqueous phase wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried (Na₂SO₄), and concentrated. The residue was purifiedusing column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1).Yield: 2.0 g, 96%. ¹H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.34(s, 1H), 4.26-4.13 (m, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 2.46-2.32 (m,2H), 2.16-1.98 (m, 3H), 1.90-1.78 (m, 1H).

Compound 219.5. 5-Cyano-2-cyclobutyl-4-methylbenzohydrazide. To asolution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (219.4, 2.0 g,8.73 mmol) in EtOH (10 ml) was added anhydrous hydrazine (2 ml, excess)at room temperature. The mixture was heated at 90° C. overnight. Aftercooling to ambient temperature, the mixture was partitioned betweenwater (60 ml) and EtOAc (200 ml). The EtOAc layer was washed with water(×2), brine, dried with Na₂SO₄, and concentrated to give the product asa white solid. Yield: 1.9 g, 95%. m/z (ES +) 230 (M+H)⁺. ¹H NMR (400MHz, Chloroform-d) δ 7.52 (s, 1H), 7.32 (s, 1H), 6.91 (br, 1H), 4.08(br, 2H), 3.89 (m, 1H), 2.61-2.52 (m, 3H), 2.42-2.28 (m, 2H), 2.18-1.98(m, 3H), 1.91-1.78 (m, 1H).

Compound 219.6.5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile. Thetitle compound (0.55 g, white solid, 100%) was prepared using aprocedure similar to that used for the preparation of compound 217.3 andusing compound 219.5 (0.50 g) in place of compound 217.2. m/z (ES+) 255(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.45 (s, 1H),5.10 (br, 2H), 4.38 (m, 1H), 2.61 (s, 3H), 2.48-2.34 (m, 2H), 2.17-1.98(m, 3H), 1.91-1.79 (m, 1H).

Compound 219.7.4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile. Toa solution of5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile(219.6, 0.5 g, 2.0 mmol) in EtOH (40 ml) was added KOH (1.11 g, 20.0mmol). The mixture was heated at 85° C. overnight. After cooling toambient temperature, the mixture was neutralized to pH 7 with 1N HCl at0° C. and then extracted with EtOAc (×2). The combined organic layerswere dried (Na₂SO₄) and concentrated. The residue was purified usingcolumn (silica gel) chromatography (hexanes:EtOAc 1:1 to EtOAc). Yield:0.2 g, white solid, 34%. m/z (ES+) 283 (M+H)⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.84 (s, 1H), 7.35 (s, 1H), 4.48 (t, 2H), 4.19-4.10 (m,1H), 2.58 (s, 3H), 2.30-2.19 (m, 2H), 2.11-1.95 (m, 3H), 1.85-1.76 (m,1H), 1.45 (t, 3H).

Compound 219.8.4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide. To asolution of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile(219.7, 0.15 g, 0.53 mmol) in EtOH (10 ml) was added NH₄OH (0.18 ml,2.66 mmol, 14.8 N in H₂O) followed by H₂O₂ (1.8 ml, 26.6 mmol, 50% inH₂O). The mixture was stirred at room temperature overnight. The mixturewas cooled to 0° C. and quenched carefully with 1N Na₂S₂O₃ solution (26ml). The mixture was extracted with EtOAc (×2) and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified with prep-TLC (5% MeOH in CH₂Cl₂). Yield: 0.1 g, whitesolid, 62.5%. m/z (ES−) 299 (M−H)⁻.

Compound 219.9.4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. Toa solution of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide(219.8, 0.1 g, 0.33 mmol) in TFA (5 ml) was added NaNO₂ (0.046 g, 0.66mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour then at roomtemperature for 2 hours. The mixture was concentrated under reducedpressure. The residue was partitioned between EtOAc and brine. Theaqueous layer was extracted with EtOAc. The combined organic layers weredried (Na₂SO₄) and concentrated to give a clear oil. Yield: 0.1 g, 100%.m/z (ES−) 300 (M−H)⁻.

Compound 219.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.A solution of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 219.9, 40 mg. 0.13 mmol), DIEA (0.07 ml, 0.39 mmol), HOBT (34mg, 0.19 mmol, with 20% water), EDCI (38 mg, 0.19 mmol), and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 36 mg, 0.16mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at roomtemperature. The reaction mixture was then diluted with 50 mL of ethylacetate and washed with 2×20 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was applied onto a silica gel prep-TLC plate and developed usingethyl acetate/hexanes (1:1) to yield 0.1 g (68%) of the title compoundas a white solid. m/z (ES+) 470 (M+H)⁺.

Compound 220.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 219), using compound 11.2 HCl salt in place of compound 1.5.m/z (ES +) 488 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 11.10 (br s, 1H),7.72-7.63 (m, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.42 & 7.33 (2 singlets,amide rotamers, Ar—H, 1H), 7.25 (s, 1H), 4.86 (br d, J=11.2 Hz, 1H),4.41 (q, J=7.1 Hz, 2H), 4.17-4.03 (m, 1H), 3.61-3.38 (m, 2H), 3.29-3.14(m, 1H), 2.46-1.70 (m, 13H), 1.45 (t, J=7.2 Hz, 3H).

Compound 221.(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluoro-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 219). m/z (ES+) 531 (M+H)⁺.

Compound 222.1.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile(compound 219.7), except MeOH was used as the solvent instead of EtOH.m/z (ES+) 269 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.96 (br, 1H),7.82 (s, 1H), 7.35 (s, 1H), 4.11 (s, 3H), 4.15-4.05 (m, 1H), 2.59 (s,3H), 2.31-2.16 (m, 2H), 2.14-1.89 (m, 3H), 1.87-1.71 (m, 1H).

Compound 222.2.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide. Thetitle compound was prepared using standard chemical manipulations andprocedures similar to those used for the preparation of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide(compound 219.8) but using compound 222.1 in place of compound 219.7.m/z (ES+) 287 (M+H)⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 7.50 (s, 1H), 7.33(s, 1H), 4.03 (s, 3H), 3.95-4.05 (m, 1H), 2.51 (s, 3H), 2.23-2.11 (m,2H), 2.11-1.88 (m, 3H), 1.83-1.71 (m, 1H).

Compound 222.3.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 219.9) but using compound 222.2 in place of compound 219.8.m/z (ES+) 287 (M+H)⁺.

Compound 222.4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.A solution of4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 222.3, 60mg, 0.21 mmol), DIEA (0.11 ml, 0.63 mmol), HOBT (53mg, 0.32 mmol, with 20% water), EDCI (60 mg, 0.32 mmol) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 47 mg, 0.21mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at roomtemperature. The reaction mixture was then diluted with 50 mL of ethylacetate and washed with 2×20 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was applied onto a silica gel prep-TLC plate and developed usingethyl acetate/hexanes (1:1) to yield 21.0 mg (22%) of the title compoundas a white solid. m/z (ES+) 456 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ11.54-10.86 (br s, 1H), 7.60 (d, 2H), 7.38-7.20 (m, 4H), 5.04-4.92 (m,1H), 4.06 (s, 3H), 4.14-4.00 (m, 1H), 3.62 (d, 1H), 3.15-3.03 (m, 1H),2.93-2.76 (m, 2H), 2.38 and 2.30 (2 singlets, amide rotamers, ArCH₃,3H), 2.34-2.22(m, 1H), 2.20-2.06 (m, 2H), 2.05-1.84 (m, 3H), 1.61-1.45(m, 1H).

Compound 223.4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 222) but using compound 11.2 HCl salt in place of compound1.5. m/z (ES+) 474 (M+H)⁺.

Compound 224.(4-Cyclobutyl-5-(5-methoxy-4H-4-triazol-3-yl)-2-methylphenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(222). m/z (ES+) 499 (M+H)⁺.

Compound 225.(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluoro-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(Compound 222). m/z (ES+) 517 (M+H)⁺.

Compound 226.3. Methyl 4-cyclopropyl-2-ethylbenzoate. To a stirredmixture of ZnBr₂ (37.0 g, 164 mmol, 3.99 equiv) in tetrahydrofuran (150mL) under nitrogen was added bromo(cyclopropyl)magnesium (3.28 M in THF,50 mL, 4.00 equiv) dropwise at 0° C. After stirring at 15 minutes at 0°C., the temperature was lowered to −30° C. followed by the dropwiseaddition of a solution of Pd(dppf)Cl₂ (2.00 g, 2.73 mmol, 0.07 equiv) intetrahydrofuran (50 mL) and a solution of methyl 4-bromo-2-ethylbenzoate(compound 181.2, 10.0 g, 41.1 mmol, 1.00 equiv) in tetrahydrofuran (50mL). The resulting solution was warmed slowly to 25° C. and stirred for15 h, then carefully quenched by slow addition of 100 mL of NH₄Cl (aq.sat.). The mixture was extracted with 2×100 mL of ethyl acetate and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:30) as eluent toyield 7.50 g (89%) of methyl 4-cyclopropyl-2-ethylbenzoate as a lightyellow oil.

Compound 226.4. Methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate. To around-bottom flask was added a solution of methyl4-cyclopropyl-2-ethylbenzoate (compound 226.3, 5.00 g, 24.5 mmol, 1.00equiv) in AcOH (40 mL). I₂ (6.80 g. 26.8 mmol, 1.10 equiv), NaIO₄ (2.60g, 12.2 mmol. 0.50 equiv), and sulfuric acid (400 mg, 4.08 mmol, 0.15equiv) were added to the reaction. The resulting solution was stirredfor 2 h at 50° C. After cooling to ambient temperature, the reaction wascarefully quenched with Na₂S₂O₃ (aq., sat.). The mixture was extractedwith 2×100 mL of ethyl acetate, and the combined organic layers weredried over sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with petroleumether/ethyl acetate (20:1) as eluent to furnish 4.00 g (49%) of methyl4-cyclopropyl-2-ethyl-5-iodobenzoate as a yellow oil.

Compound 226.5. 4-Cyclopropyl-2-ethyl-5-iodobenzoic acid. To a solutionof methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate (compound 226.4, 2.50 g,7.57 mmol, 1.00 equiv) in methanol (40 mL) was added aqueous sodiumhydroxide (3.10 g, 77.5 mmol, 10.0 equiv, in 10 mL water). The resultingmixture was stirred for 15 h at 60° C. in an oil bath. After cooling toambient temperature, the organic solvent was removed under reducedpressure and pH of the remaining aqueous layer was adjusted to 4 withhydrogen chloride (aq, 1 M). The solids were collected by filtration anddried in an oven under reduced pressure to yield 2.20 g (92%) of4-cyclopropyl-2-ethyl-5-iodobenzoic acid as a white solid.

Compound 226.6. 4-Cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid.To a solution of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid (compound226.5, 500 mg, 1.58 mmol, 1.00 equiv) in THF/Et₂O (10/10 mL) undernitrogen at −78° C. was added dropwise n-butyllithium (2.5 M, 1.88 mL,3.00 equiv) over 3 min. After stirring for 10 min at −78° C., methylchloroformate (230 mg, 2.43 mmol, 1.50 equiv) was added dropwise at −78°C. The resulting solution was stirred for 40 min at −78° C., then warmedslowly to −35° C. The reaction was carefully quenched with 2 mL ofwater. The pH was adjusted to ˜4-5 with hydrogen chloride (aq., 1 M).The resulting mixture was extracted with 3×20 mL of ethyl acetate andthe combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield 400 mg the title compound as a yellow solid.

Compound 226.7. Methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate.To a solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid(compound 226.6, 150 mg, 0.600 mmol, 1.00 equiv) inN,N-dimethylformamide (15 mL) were added4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2, 150mg, 0.620 mmol, 1.00 equiv), DIPEA (450 mg, 3.49 mmol, 6.00 equiv), andHBTU (300 mg, 0.790 mmol, 1.30 equiv). The resulting solution wasstirred for 4 h at 20° C., then quenched by the addition of 20 mL ofbrine. The resulting mixture was extracted with 4×30 mL of ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified via silicagel column with ethyl acetate/petroleum ether (1:3) as eluent. Thisresulted in 0.200 g (76%) of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoateas a light yellow solid.

Compound 226.8.5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide.To a solution of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate(compound 226.7, 200 mg, 0.460 mmol, 1.00 equiv) in ethanol (15 mL) wasadded hydrazine hydrate (80%, 5 mL). The resulting solution was stirredat 80° C. for 15 h. After cooling to ambient temperature, the reactionwas quenched with 50 mL of water, then extracted with 3×50 mL ofdichloromethane. The combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo to yield 150 mg (75%) of5-(4(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazideas a colorless oil.

Compound 226.9.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclopropyl-2-ethylbenzoyl)-4-fluoropiperidin4-yl)benzonitrile.The title compound (50 mg, white solid, 95%) was prepared using aprocedure similar to that used for the preparation of compound 217.3 andusing compound 226.8 (50 mg) in place of compound 217.2.

Compound 226.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound (50 mg, white solid, 95%) was prepared using aprocedure similar to that used for the preparation of compound 219.7 andusing compound 226.9 (300 mg) in place of compound 219.6. The crudeproduct (˜30 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (46.0% CH₃CN up to 57.0% in8 min, up to 100.0% in 1 min, down to 46.0% in 1 min); Detector, Waters2489 254 & 220 nm. The fractions containing pure compound were combinedand lyophilized to yield 15 mg of the title compound as a white solid.m/z (ES+) 474 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.73 (d, 2H),7.65-7.57 (m, 2H), 7.46-7.32 (m, 1H), 7.03 (s, 1H), 4.85-4.73 (m, 1H),4.00 (s, 3H), 3.48-3.32 (m, 2H), 3.28-3.21 (m, 1H), 2.71-2.62 (m, 2H),2.28-2.14 (m, 2H), 2.10-1.80 (m, 3H), 1.28-1.20 (m, 3H), 0.97-0.94 (m,2H), 0.75-0.50 (m, 2H).

Compound 227.4-(1-(4-Cyclopropyl-5-(5-ethoxy-4-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 226). m/z (ES+) 488 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ7.80-7.78 (m, 2H), 7.70-7.63 (m, 2H), 7.51 (m, 1H), 7.07 (s, 1H),4.89-4.82 (m, 1H), 4.40 (app t, 2H), 3.57-3.52 (m, 2H), 3.28-3.25 (m,1H), 2.80-2.50 (m, 2H), 2.40-2.10 (m, 4H), 1.95-1.80 (m, 1H), 1.45 (t,3H), 1.32-1.22 (m, 3H), 1.01-0.99 (m, 2H), 0.73-0.73 (m, 2H).

Compound 228.1. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate.To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6,500 mg, 2.01 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL). HBTU(1.53 g, 4.03 mmol, 2.00 equiv), DIEA (780 mg, 6.04 mmol, 3.00 equiv)were added to the reaction solution, and it was stirred for 5 min at 25°C. 4-(piperidin-4-yl)benzonitrile (compound 1.5, 410 mg, 2.20 mmol, 1.10equiv) was added to the above mixture. After stirring for 15 h at 25°C., the reaction was quenched by the addition of water. The mixture wasextracted with 100 mL of ethyl acetate and the combined organic layerswere washed with 4×40 mL of brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (4:1) as eluentto furnish 0.830 g (99%) of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoateas a colorless oil.

Compound 228.2.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide.To a round-bottom flask was added a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate(compound 228.1, 830 mg, 1.99 mmol, 1.00 equiv) in ethanol (15 mL).Hydrazine (5 mL, 100 equiv) was added to the reaction. The resultingsolution was stirred for 15 h at 100° C., then concentrated in vacuo.The residue was extracted with 100 mL of dichloromethane and thecombined organic layers were washed with 1×30 mL of brine, dried overanhydrous sodium sulfate and concentrated in vacuo. This resulted in0.800 g (96%) of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazideas a white solid.

Compound 228.3. 4-(1-(5-(5-Amino-1,3,4-oxadiazol,y-4-cyclopropyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile. The titlecompound (750 mg, light brown solid, 94%) was prepared using a proceduresimilar to that used for the preparation of compound 217.3 and usingcompound 228.2 (750 mg) in place of compound 217.2.

Compound 228.4.4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide.The title compound (80 mg, yellow solid, 36%) was prepared using aprocedure similar to that used for the preparation of compound 219.7 andusing compound 228.3 (200 mg) in place of compound 219.6.

Compound 228.4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide(compound 228.4, 80.0 mg, 0.160 mmol, 1.00 equiv) in dichloromethane (10mL). Trifluoroacetic anhydride (34.0 mg, 0.160 mmol, 1.00 equiv) andtriethylamine (33.0 mg. 0.330 mmol, 2.00 equiv) were added dropwise tothe stirred mixture. The resulting solution was stirred for 2 h at 25°C., then washed with 1×10 mL of brine. The aqueous layer was extractedwith 2×20 mL of dichloromethane and the combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct (30 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (42% CH₃CN up to 57% in 8min, up to 100% in 1.5 min, down to 42% in 1 min); Detector, Waters 2489254 & 220 nm. The fractions containing pure compound were combined andlyophilized to yield 15 mg (20%) of the title compound as a an off-whitesolid. m/z (ES+) 470 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.64 (d,2H), 7.46-7.28 (m, 3H), 7.02-7.01 (m, 1H), 4.89-4.80 (m, 1H), 4.40-4.33(m, 2H), 3.58-3.56 (m, 1H), 3.27-3.25 (m, 1H), 3.04-2.90 (m, 2H),2.73-2.58 (m, 2H), 2.31-2.29 (m, 1H), 1.94-1.96 (m, 1H), 1.82-1.78 (m,3H), 1.45 (t, 3H), 1.32-1.12 (m, 3H), 0.98-0.88 (m, 2H), 0.71-0.68 (m,2H).

Compound 229.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound228. m/z (ES+) 456 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.64 (d, 2H),7.43-7.27 (m, 3H), 7.03-7.02 (m, 1H), 4.0 (s, 3H), 3.59-3.55 (m, 1H),3.28-3.27 (m, 1H), 3.04-2.98 (m, 2H), 2.97-2.56 (m, 2H), 2.53-2.29 (m,1H), 2.0-1.98 (m, 1H), 1.76-1.42 (m, 3H), 1.30-1.16 (m, 3H), 0.99-0.94(m, 2H), 0.70-0.64 (m, 2H).

Compound 230.1. 4-Cyclobutyl-5-iodo-2-methylbenzoic acid. To a solutionof methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 35.0 g,106 mmol, 1.00 equiv) in methanol (200 mL) at 0-5° C. was added dropwiseaqueous sodium hydroxide (12.7 g, 318 mmol, 3.00 equiv in 100 mL water).The resulting mixture was stirred for 3 h at 60° C. After cooling toambient temperature, the organic solvent was then removed under reducedpressure. The pH of the remaining aqueous phase was adjusted to withhydrogen chloride (aqueous, 2 M). The resulting solids were collected byfiltration and dried in an oven under reduced pressure to yield 31.0 g(93%) of the title compound as a white solid.

Compound 230.2. 4-Cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid.To a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound230.1, 3.00 g, 9.49 mmol, 1.00 equiv) in THF (40 mL) under nitrogen at−78° C. was added dropwise n-BuLi (9.5 mL, 2.50 equiv, 2.5 M in THF).After 10 minutes, a solution of dimethyl carbonate (2.56 g, 28.4 mmol,3.00 equiv) in THF (10 mL) was added dropwise at −78° C. The resultingsolution was stirred for 1 h at −78° C., then carefully quenched by slowaddition of 50 mL of water. The pH was adjusted to ˜4 with hydrogenchloride (aq., 1 M). The resulting mixture was extracted with 2×80 mL ofethyl acetate, the combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:10-1:2) as eluent to furnish 1.30 g (55%) of4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid as a white solid.

Compound 230.3. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate.To a round-bottom flask was added a solution of4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 230.2,2.10 g, 8.46 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL).4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.88 g, 8.44mmol, 1.00 equiv), EDC.HCl (3.22 g, 16.8 mmol, 2.00 equiv), and4-dimethylaminopyridine (3.10 g, 25.4 mmol, 3.00 equiv) were added tothe reaction. The resulting solution was stirred overnight at 25° C.,then diluted with 100 mL of ethyl acetate. The mixture was washed with2×30 mL of NH₄Cl (aq., sat.) and 2×30 mL of brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(0:1-1:3) as eluent to yield 3.20 g (91%) of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoateas a white solid.

Compound 230.4.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydrazide.The title compound (660 mg, white solid, 66%) was prepared using aprocedure similar to that used for the preparation of compound 219.5 andusing compound 230.3 (1.00 g) in place of compound 219.4.

Compound 230.4-(1-(4-Cyclobutyl-5-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydrazide(compound 230.4, 150 mg, 0.360 mmol, 1.00 equiv) in dioxane (5 mL).MeSO₃H (7 mg, 0.07 mmol, 0.20 equiv), and 1,1,1-triethoxypropane (190mg, 1.08 mmol, 3.00 equiv) were added to the reaction. The resultingsolution was stirred for 20 min at 110° C., then cooled to roomtemperature and diluted with 50 mL of ethyl acetate. The organic layerwas washed with 2×20 mL of water, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product (200 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (64.0% CH₃CN up to 76.0% in 6 min, up to 100.0% in 4 min,down to 64.0% in 1 min); Detector, Waters 2489 254 & 220 nm. Thefractions containing pure compound were combined and lyophilized toyield 129 mg (79%) of the title compound as a white solid. (ES+) 455(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.73-7.67 (m, 3H), 7.52-7.48 (m,3H), 5-4.94 (m, 1H), 4.25-4.20 (m, 1H), 3.60-3.58 (m, 1H), 3.33-3.24 (m,1H), 3.05-2.97 (m, 4H), 2.49 and 2.30 (2 singlets, amide rotamers, CH₃,3H), 2.39-2.34 (m, 2H), 2.19-1.91 (m, 4H), 1.88-1.66 (m, 4H), 1.49-1.42(t, 3H).

Compound 231.1. Methyl 4-ethenyl-2-methylbenzoate. To a round-bottomflask, which was purged and maintained with a nitrogen atmosphere, wasadded a solution of methyl 4-bromo-2-methylbenzoate (compound 152.1,14.0 g, 61.1 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL).Tributyl(ethenyl)stannane (29.3 g, 92.4 mmol, 2.00 equiv) and Pd(PPh₃)₄(7.10 g, 6.14 mmol, 0.10 equiv) were added to the reaction. Theresulting mixture was stirred overnight at 100° C. in an oil bath. Aftercooling to room temperature, the mixture was diluted with 400 mL ofethyl acetate. The organic layer was washed with 2×400 mL of NH₄Cl (aq.)and 2×400 mL of brine, dried over anhydrous sodium sulfate, thenconcentrated in vacuo. The crude product was purified by CombiFlash withthe following conditions (IntelFlash-1): mobile phase, petroleumether/ethyl acetate=1:0 increasing to petroleum ether/ethylacetate=100:1 within 20 min; Detector, UV 254 nm. This resulted in 6.81g (63%) of methyl 4-ethenyl-2-methylbenzoate as a colorless oil.

Compound 231.2. Methyl 2-methyl-4-(3-oxocyclobutyl)benzoate. To asolution of N,N-dimethylacetamide (5.5 mL) in DCE (20 mL) under nitrogenat −15° C. was added a solution of trifluoromethanesulfonic anhydride(10 mL) in DCE (50 mL) dropwise. The mixture was then stirred for 10 minat −15° C. to make solution A. To another flask was added methyl4-ethenyl-2-methylbenzoate (compound 231.1, 5.30 g, 0.03 mol, 1.00equiv). A solution of 2,4,6-trimethylpyridine (5.5 mL) in DCE (80 mL)was added dropwise at −15° C. The resulting mixture was added intosolution A dropwise under an inert atmosphere of nitrogen. The resultingsolution was stirred overnight at 80° C. After cooling to ambienttemperature, the mixture was carefully quenched with water. Theresulting mixture was extracted with 2×200 mL of ethyl acetate, and thecombined organic layers were washed with 3×400 mL of brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:50-1:5) as eluent to furnish 2.95 g (45%) ofmethyl 2-methyl-4-(3-oxocyclobutyl)benzoate as a brown oil.

Compound 231.3. Methyl 4-(3,3-difluorocyclobutyl)-2-methylbenzoate. To around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of methyl2-methyl-4-(3-oxocyclobutyl)benzoate (compound 231.2, 3.00 g, 13.8 mmol,1.00 equiv) in dichloromethane (100 mL). DAST (22.2 g, 137 mmol, 10.00equiv) was added to the reaction mixture. The resulting solution wasstirred overnight at 25° C., then carefully quenched by slowly adding(dropwise at first) 500 mL of sodium bicarbonate (aq.) and ice. Themixture was extracted with 300 mL of ethyl acetate and the combinedorganic layers were washed with 2×300 mL of sodium bicarbonate (aq.) and2×300 mL of brine, dried over anhydrous sodium sulfate, and concentratedin vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:20) as eluent tofurnish 3.00 g (91%) of methyl4-(3,3-difluorocyclobutyl)-2-methylbenzoate as a brown oil.

Compound 231.4. Methyl4-(3,3-difluorocyclobutyl)-5-iodo-2-methylbenzoate. The title compound(3.02 g, yellow solid, 66%) was prepared using a procedure similar tothat used for the preparation of compound 181.4 and using compound 231.3(3.00 g) in place of compound 181.3.

Compound 231.5. 4-(3,3-Difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid. The title compound wassynthesized using standard chemical manipulations and procedures similarto those used for the preparation of compound 164.1 using compound 231.4in place of compound 152.3.

Compound 231.4-(1-(4-(3,3-Difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 231.5, 211 mg, 0.660 mmol, 1.00 equiv) inN,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 146 mg, 0.660 mmol, 1.00 equiv), EDC.HCl(252 mg, 1.31 mmol, 2.00 equiv) and 4-dimethylaminopyridine (160 mg,1.31 mmol, 2.00 equiv) were added to the reaction. The resultingsolution was stirred for 3 h at 30° C. in an oil bath, then diluted with30 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine,dried over anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct (448 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (48.0% CH₃CN up to 62.0% in6 min, up to 100.0% in 4 min, down to 48.0% in 2 min); Detector, Waters2489 254 & 220 nm. The fractions containing pure compound were combinedand lyophilized to yield 186 mg (58%) of the title compound as a whitesolid, (ES+) 490 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.68 (d, J=8Hz, 2H), 7.59-7.44 (m, 4H), 4.89-4.80 (m, 1H), 4.03-3.98 (m, 1H),3.67-3.61 (m, 1H), 3.28-3.24 (m, 1H), 3.04-3.00 (m, 2H), 2.97-2.89 (m,2H), 2.87-2.83 (m, 2H), 2.62-2.60 (m, 2H), 2.48 and 2.38 (2 singlets,amide rotamers, ArCH₃, 3H), 2.05-2.00 (m, 1H), 1.88-1.58 (m, 3H), 1.41(t, 3H).

Compound 232.1. Methyl5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate. Amixture of 3-bromo-N,N-dimethyl-2-oxopropanamide (246 mg), methyl5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 237mg), and potassium carbonate (311 mg) in acetonitrile (12 ml) was heatedto reflux for 48 hours. After cooling to ambient temperature the mixturewas concentrated. The residue was dissolved in EtOAc and washed withbrine, dried over MgSO₄, concentrated, and purified by flashchromatography (SiO₂; EtOAc) to give 88 mg of the title compound. m/z(ES+) 302 (M+H)⁺.

Compound 232.2.5-(5-(Dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic acid.Methyl 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate(compound 232.1, 113 mg, 0.37 mmol) was dissolved in 2N LiOH aqueous (1ml) and tetrahydrofuran (THF) (5 ml) and heated to 50° C. for 16 hours.After cooling to ambient temperature, the organic solvent was removed invacuo. The pH of the remaining aqueous layer was adjusted with 2N HCl topH 3-4. The resulting precipitate was collected by filtration and driedto afford 56 mg of5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic acid(53%). m/z (ES+) 288 (M+H)⁺.

Compound 232.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-1H-imidazole-5-carboxamide.A mixture of above acid (compound 232.2, 56 mg, 0.2 mmol),4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 45 mg, 0.2mmol), HBTU (152 mg, 0.4 mmol), and DIEA (105 ul, 0.6 mmol) in DMF (2ml) was stirred at room temperature for 16 hours. The reaction wasdiluted with brine and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄ and concentrated. The residue waspurified by flash chromatography (SiO₂; 4% Methanol in EtOAc) to yield44 mg of a foam (48%). m/z (ES+) 456 (M+H)⁺.

Compound 233.4-(1-(2,4-Dimethyl-5-(5-(morpholine-4-carbonyl)-1H-imidazol-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-1H-imidazole-5-carboxamide(compound 232). m/z (ES+) 498 (M+H)⁺.

Compound 234.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoicacid. To a a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate(compound 230.3, 1.50 g, 3.60 mmol, 1.00 equiv) in methanol (10 mL) wasadded aqueous sodium hydroxide (577 mg, 14.4 mmol, in 5 mL water)dropwise at 0° C. The resulting solution was stirred for 2 h at 60° C.in an oil bath. After cooling to ambient temperature, the organicsolvent was removed under reduced pressure. The pH of the remainingaqueous layer was adjusted to 3-4 with hydrogen chloride (aq., 2 M). Theresulting solids were collected by filtration and dried in an oven underreduced pressure to yield 1.20 g (83%) of the title compound as a whitesolid. m/z (ES+) 403 (M+H)⁺.

Compound 235.1.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoylchloride. To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoicacid (compound 234, 500 mg, 1.24 mmol, 1.00 equiv) in dichloromethane (5mL). Oxalyl chloride (317 mg, 2.50 mmol, 2.00 equiv) andN,N-dimethylformamide (˜5 mg) were added dropwise to the mixture. Theresulting solution was stirred for 1 h at 40° C., then concentrated anddried under reduced pressure to yield 480 mg (92%) of the title compoundas a light yellow oil.

Compound 235.2.4-(1-(5-(2-Bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a a solution of TMSCHN₂ (2 M in hexane) (0.476 mL, 2.00 equiv) indichloromethane (10 mL) under nitrogen at 0° C. was added dropwise asolution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoylchloride (compound 235.1, 200 mg, 0.480 mmol, 1.00 equiv) indichloromethane (3 mL). The resulting mixture was stirred overnight at25° C. HBr (40%) (0.154 mL, 1.50 equiv) was then added dropwise at 0° C.and the mixture was stirred for another 2 h at 0° C., then diluted with50 mL of dichloromethane. The organic layer was washed with 2×20 mL ofwater and 1×20 mL of brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (0:1-1:50-1:5) aseluent to furnish 200 mg (88%) of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrileas a yellow oil.

Compound 235.4-(1-(4-Cyclobutyl-5-(2-ethyl-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 235.2, 100 mg, 0.210 mmol, 1.00 equiv) in CH₃CN (5 mL).Propionimidamide hydrochloride (22.8 mg, 1.00 equiv) and potassiumcarbonate (86.6 mg, 0.63 mmol, 3.00 equiv) were added to the reaction.The resulting solution was stirred for 3 h at 80° C., then cooled toroom temperature and concentrated in vacuo. The residue was dissolved in20 mL of water. The mixture was extracted with 2×20 mL of ethyl acetateand the combined organic layers were dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product (˜100 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (29.0% CH₃CN up to 43.0% in 7 min, up to 100.0% in 3 min,down to 9.0% in 2 min); Detector, Waters 2489 254 & 220 nm. Thefractions containing pure compound were combined and lyophilized toyield 43 mg (44%) of the title compound as a white solid. m/z (ES+) 453(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.68 (d with fine structure, J=7.8Hz, 2H), 7.56-7.53 (m, 4H), 7.30 and 7.20 (2 singlets, amide rotamers,Ar—H, 1H), ˜4.9 (1H partially obscured by water peak), 3.84-3.70 (m,1H), 3.70-3.53 (m, 1H), 3.33-3.19 (m, 1H partially obscured by methanolsolvent peak), 3.13-2.92 (m, 4H), 2.48 & 2.38 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.29-2.11 (m, 4H), 2.11-1.93 (m, 2H), 1.93-1.72(m, 3H), 1.72-1.53 (m, 1H), 1.45 (t, 3H).

Compound 236.1.4-(1-(5-(2-Bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 235.2) but using compound 11.2 HCl salt instead of compound1.5.

Compound 236.4-(1-(4-Cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.To a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 236.1, 40 mg, 0.08 mmol, 1.00 equiv) in CH₃CN (10 mL).Acetimidamide hydrochloride (7.6 mg, 0.08 mmol, 1.00 equiv) andpotassium carbonate (33.4 mg, 0.24 mmol, 3.00 equiv) were added to thereaction. The resulting solution was stirred for 2 h at 80° C. in an oilbath, then cooled to ambient temperature and concentrated under reducedpressure. The residue was dissolved in 50 mL of ethyl acetate. Theorganic layer was washed with 2×20 mL of water, 2×20 mL of brine, driedover anhydrous sodium sulfate and concentrated under vacuum. The crudeproduct (˜50 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (29.0% CH₃CN up to 43.0% in8 min, up to 100.0% in 2 min, down to 29.0% in 2 min); Detector, Waters2489 254 & 220 nm. The fractions containing pure compound were combinedand lyophilized to yield 13 mg (35%) of the title compound as a whitesolid. m/z (ES+) 457 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.78 (d, 2H),7.65 (d, 2H), 7.50-7.46 (m, 2H), 7.35 and 7.23 (2 s, amide rotamers,1H), 4.91-4.83 (m, 1H), 3.76-3.63 (m, 1H), 3.54-3.49 (m, 2H), 3.32-3.30(m, 1H), 2.70 (s, 3H), 2.49 and 2.39 (2 singlets, amide rotamers, ArCH₃,3H), 2.34-2.28 (m, 7H), 1.98-1.80 (m, 3H).

Compound 237.1. N′-Hydroxy-3-methoxypropanimidamide. Into a round-bottomflask, was placed a solution of 3-methoxypropanenitrile (10.0 g, 118mmol, 1.00 equiv) in ethanol (20 mL). NH₂OH (50% in H₂O) (10 mL) wasadded to the reaction. The resulting solution was stirred overnight at90° C. in an oil bath, then cooled to ambient temperature andconcentrated under reduced pressure. The residue was diluted with 30 mLof H₂O and washed with 2×20 mL of ethyl acetate. The aqueous layers werecombined and concentrated under reduced pressure to yield 10.0 g (65%)of the title compound as a colorless oil.

Compound 237.2. 3-Methoxypropanimidamide hydrochloride. Into around-bottom flask, was placed a solution ofN′-hydroxy-3-methoxypropanamidine (compound 237.1, 10.0 g, 76.2 mmol,1.00 equiv, 90%) in AcOH (50 mL). Acetic anhydride (9.50 g, 93.1 mmol,1.10 equiv) was added dropwise and the resulting mixture was stirred for30 min at room temperature. After purging the flask with nitrogen,palladium on carbon (10%, 60% water, 5 g) was added. The flask wascarefully purged with nitrogen again and the atmosphere was then changedto hydrogen. The mixture was stirred overnight at 20° C. underatmospheric pressure of hydrogen. After purging the system withnitrogen, the solids were then removed by filtration and the filtratewas concentrated under reduced pressure. The residue was diluted with 50mL of H₂O. The pH value of the solution was adjusted to 2-3 withhydrogen chloride (12 mol/L), then washed with 2×30 mL of ethyl acetate.The aqueous layers were combined and concentrated under reduced pressureto furnish 5.00 g (40%) of the title compound as an off-white solid.

Compound 237.4-(1-(4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol.-5-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 236) and using 237.2 in place of acetimidamide hydrochloride.m/z (ES+) 501 (M+H)⁺.

Compound 238.1. Methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate. To asolution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (152.3, 5.00 g,15.1 mmol, 1.00 equiv) in DMSO (50 mL) under nitrogen were added1-(ethenyloxy)butane (3.03 g, 30.3 mmol, 2.00 equiv), DPPP (624 mg, 1.51mmol, 0.10 equiv), Pd(OAc)₂ (324 mg, 1.51 mmol, 0.10 equiv), and TEA(3.06 g, 30.2 mmol, 2.00 equiv). The resulting mixture was stirredovernight at 120° C. under nitrogen, then cooled to ambient temperatureand diluted with water. The pH was adjusted to 1 with hydrogen chloride(aq., 6 M). The resulting mixture was diluted with 200 mL of ethylacetate, washed with brine (3×200 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:30) as eluent tofurnish 2.28 g (61%) of the title compound as a yellow oil.

Compounds 238.2 and 238.3. Methyl5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoate and methyl4-cyclobutyl-5-(2,2-dibromoacetyl)-2-methylbenzoate. To a solution ofmethyl 5-acetyl-4-cyclobutyl-2-methylbenzoate (238.1, 500 mg, 1.83 mmol,1.00 equiv, 90%) in chloroform (5 mL) was added dropwise Br₂ (325 mg,2.03 mmol. 1.00 equiv) (CAUTION: exotherin reaction with significantevolution of HBr). The resulting mixture was stirred for 3 h at 25° C.,and then quenched by the addition of 5 mL of H₂O. The mixture was thenextracted with 50 mL of ethyl acetate. The organic phase was washed with2×10 mL of Na₂S₂O₃ (aq., sat.) followed by 1×20 mL of brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toyield 500 mg of a mixture of the title compounds as a yellow oil.

Compound 238.4. Methyl4-cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoate.Into around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of a mixture of compounds238.2 and 238.3 (500 mg, ˜0.6 mmol, 80%), potassium carbonate (640 mg,3.00 equiv), 3-methoxypropanimidamide hydrochloride (compound 237.2, 213mg, 1.54 mmol) in acetonitrile. The resulting solution was stirredovernight at 80° C. in an oil bath, then cooled to ambient temperatureand concentrated under reduced pressure. The residue was diluted with 60mL of ethyl acetate. The organic layer was washed with 2×25 mL of water,2×25 mL of brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (2:1) as eluent tofurnish 90 mg (43%) of the title compound as a yellow solid.

Compound 238.5.4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoicacid. A mixture of compound 238.4, 90 mg, 0.25 mmol, 1.00 equiv, 90%)and aqueous sodium hydroxide (44 mg, 1.10 mmol, 4.00 equiv in 1 mL ofwater) in methanol (3 mL) was stirred for 2 h at 60° C. After cooling toambient temperature, the methanol was removed under reduced pressure.The pH of the residual aqueous layer was adjusted to 3-4 with hydrogenchloride (aqueous, 2 M). The resulting mixture was concentrated underreduced pressure to yield 80 mg (crude) of the title compound as ayellow solid.

Compound 238.4-(1-(4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of compound 238.5 (80 mg,0.23 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL).4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 54 mg, 0.24mmol, 1.00 equiv), EDC.HCl (93 mg, 0.49 mmol, 2.00 equiv), and4-dimethylaminopyridine (59 mg, 0.48 mmol, 2.00 equiv) were added to thesolution. The resulting mixture was stirred for 3 h at 30° C., thendiluted with 50 mL of ethyl acetate. The organic layer was washed with2×20 mL of water, 2×20 mL of brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with chloroform/methanol (20:1) aseluent. The product (˜50 mg) was further purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (29%CH₃CN up to 43% in 8 min, up to 100% in 6 min, down to 29% in 1 min);Detector, Waters 2489 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 20.6 mg (19%) of thetitle compound as a white solid. m/z (ES +) 483 (M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 236,237, and 238:

Cmpnd m/z # Compound Name Compound Structure (ES+) 2394-(1-(4-cyclobutyl- 5-(2- (methoxymethyl)- 1H-imidazol-5-yl)-2-methylbenzoyl)-4- fluoropiperidin-4- yl)benzonitrile

487 (M + H)⁺ 240 4-(1-(4-cyclobutyl- 5-(2- (methoxymethyl)-1H-imidazol-5-yl)- 2-methylbenzoyl) piperidin-4- yl)benzonitrile

469 (M + H)⁺ 241 4-(1-(4-cyclobutyl- 3-(2-methyl-1H- imidazol-5-yl)benzoyl) piperidin-4-yl) benzonitrile

425 (M + H)⁺ 242 4-(1-(4-cyclobutyl- 2-methyl-5-(2- methyl-1H-imidazol-5- yl)benzoyl) piperidin-4-yl) benzonitrile

439 (M + H)⁺ 243 4-(1-(4-cyclobutyl- 3-(2-(2- methoxyethyl)-1H-imidazol-5- yl)benzoyl)-4- fluoropiperidin-4- yl)benzonitrile

487 (M + H)⁺ 244 4-(1-(4-cyclobutyl- 3-(2-(2- methoxyethyl)-1H-imidazol-5- yl)benzoyl)piperidin- 4-yl)benzonitrile

469 (M + H)⁺

Compound 245.1. Methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoatehydrochloride. The title compound was prepared using standard chemicalmanipulations and procedures similar to those used for preparation ofmethyl 5-(N′-hydroxycarbamimidoyl)-2,4-dimethylbenzoate (compound 2.4)and methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound2.5) using methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4)instead of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3).

Compound 245.2. Methyl4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate. To around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of methyl5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound245.1, 350 mg, 1.11 mmol, 1.00 equiv, 90%) in ACN (50 mL).1-Bromobutan-2-one (186 mg, 1.23 mmol, 1.00 equiv) and potassiumcarbonate (513 mg, 3.53 mmol, 3.00 equiv, 95%) were added to thereaction. The resulting solution was stirred overnight at 80° C. Aftercooling to ambient temperature, the mixture was diluted with ethylacetate and washed with 3×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:5) as eluent to furnish 290 mg (83%) of methyl4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate as a yellowsolid.

Compound 245.3. 4-Cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid. A mixture of methyl4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate (compound245.2, 200 mg, 0.600 mmol, 1.00 equiv, 90%) and sodium hydroxide (107mg, 2.68 mmol, 4.00 equiv) in a solvent mixture of methanol and water(4/2 mL) was stirred for 3 h at 60° C. After cooling to ambienttemperature, the pH was adjusted to 3-4 with hydrogen chloride (aq., 6M). The resulting mixture was concentrated in vacuo to yield 150 mg of awhite solid.

Compound 245.4-(1-(4-Cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid (compound245.3, 153 mg, 0.480 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (5mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 132 mg,0.590 mmol, 1.10 equiv), EDC.HCl (204 mg, 1.01 mmol, 2.00 equiv, 95%)and 4-dimethylaminopyridine (131 mg, 1.02 mmol, 2.00 equiv, 95%) wereadded to the reaction. The resulting solution was stirred overnight atroom temperature, then concentrated in vacuo. The residue was purifiedusing silica gel column chromatography with ethyl acetate/petroleumether (2:1) as eluent. The crude product (˜150 mg) was further purifiedby Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (28% CH₃CN up to 43% in 7 min, up to 100% in 2 min, downto 28% in 2 min); Detector, Waters 2489 254 & 220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 62 mg(29%) of the title compound as a white solid. m/z (ES+) 453 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 7.75-7.67 (m, 2H), 7.49-7.34 (m, 5H), 4.89-4.80(m, 1H), 3.75-3.72 (m, 1H), 3.64-3.59 (m, 1H), 3.27-3.23 (m, 1H),3.05-2.90 (m, 2H), 2.83 (q, 2H), 2.40 and 2.30 (2 singlets, amiderotamers, ArCH₃, 3H), 2.27-1.97 (m, 6H), 1.90-1.70 (m, 4H), 1.40 (t,3H).

Compound 246.1. 2-Methoxyacetyl chloride. To a solution of2-methoxyacetic acid (2.00 g, 22.2 mmol, 1.00 equiv) in dichloromethane(20 mL) was added dropwise (COCl)₂ (5.65 g, 2.00 equiv) inN,N-dimethylformamide (0.1 mL) (gas evolution observed). The reactionwas stirred for 1 h at 40° C. The resulting mixture was thenconcentrated under reduced pressure to yield 2.10 g (70%) of2-methoxyacetyl chloride as a yellow oil.

Compound 246.2. 1-Bromo-3-methoxypropan-2-one. To a solution of TMSCHN₂(2 M in hexane) (16 mL, 2.00 equiv) in dichloromethane (40 mL) was added2-methoxyacetyl chloride (compound 246.1, 2.10 g, 15.5 mmol, 1.00 equiv,80%) dropwise at 0° C. After stirring for 20 min, HBr (48%, 2 mL) wasadded to the reaction. The resulting solution was stirred for 30 min at25° C. The mixture was washed with 1×20 mL of brine, dried overanhydrous sodium sulfate and concentrated in vacuo. This resulted in2.30 g (71%) of 1-bromo-3-methoxypropan-2-one as a yellow oil.

Compound 246.3. Methyl4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate. Toa round-bottom flask was added a solution of1-bromo-3-methoxypropan-2-one (compound 246.2, 505 mg, 1.81 mmol, 1.00equiv, 60%) in CH₃CN (16 mL). Methyl5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound245.1, 450 mg, 1.59 mmol, 1.00 equiv) and potassium carbonate (554 mg,3.61 mmol, 3.00 equiv, 90%) were added to the reaction. The resultingsolution was stirred overnight at 80° C. under nitrogen. After coolingto ambient temperature, the reaction was carefully quenched by theaddition of water. The resulting mixture was extracted with 2×50 mL ofethyl acetate. The combined organic layers were dried (Na₂SO₄), andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:2) as eluent tofurnish 170 mg (24%) of methyl4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate asa white solid.

Compound 246.4.4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoicacid. A solution of methyl4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate(compound 246.3, 150 mg, 0.430 mmol, 1.00 equiv, 90%) and aqueous sodiumhydroxide (76.0 mg, 1.90 mmol, 4.00 equiv in 2 mL water) in methanol (4mL) was stirred for 2 h at 60° C. After cooling to ambient temperature,the organic solvent was removed under reduced pressure. The pH value ofthe remaining aquoues phase was adjusted to ˜4 with hydrogen chloride(aq., 4 M). The resulting mixture was extracted with 2×50 mL of ethylacetate, and the combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. This resulted in 120 mg (84%) of4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acidas a white solid.

Compound 246.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid(compound 246.4, 50.0 mg, 0.150 mmol, 1.00 equiv, 90%) inN,N-dimethylformamide (3 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 41.0 mg, 0.170 mmol, 1.10 equiv), EDC.HCl(64.0 mg, 0.330 mmol. 2.00 equiv), and 4-dimethylaminopyridine (41.0 mg,0.340 mmol, 2.00 equiv) were added to the reaction. The resultingsolution was stirred for 3 h at 25° C., then quenched with water andextracted with 2×30 mL of ethyl acetate. The combined organic layerswere concentrated in vacuo. The crude product (˜50 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (26.0% CH₃CN up to 42.0% in 7 min, up to 100.0% in 2 min,down to 26.0% in 1 min); Detector, Waters 2489 254 & 220 nm. Thefractions containing pure compound were combined and lyophilized toyield 18 mg (25%) of the title compound as a white solid. m/z (ES+) 469(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.73-7.64 (m, 3H), 7.52-7.32 (m, 4H),˜4.9 (1H partially obscured by water peak), 4.60 (s, 2H), 3.81-3.68 (m,1H), 3.68-3.52 (m, 1H), 3.46 (s, 3H), 3.35-3.22 (m, 1H partiallyobscured by methanol solvent peak), 3.09-2.95 (m, 2H), 2.52 & 2.41 (2singlets, amide rotamers, Ar—CH₃, 3H), 2.16-1.97 (m, 6H), 1.94-1.58 (m,4H).

Compound 247.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246), using 4-(4-fluoropiperidin-4-yl)benzonitrilehydrochloride (compound 11.2 HCl salt) instead of4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z (ES+)487 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.79-7.67 (m, 2H), 7.66 (d, 3H),7.53-7.39 (m, 2H), 4.99-4.93 (m, 1H), 4.85 (s, 2H), 3.76-3.56 (m, 3H),3.50 (s, 3H), 2.42 and 2.34 (2 singlets, amide rotamers, ArCH₃, 3H),2.27-1.97 (m, 8H), 1.92-1.81 (m, 2H), 1.35-1.26 (m, 1H).

Compound 248.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-4-methyl-1H-imidazol-2-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 501 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ7.79-7.77 (m, 2H), 7.66 (d, 2H), 7.52-7.38 (m, 2H), 4.87-4.80 (m, 1H),4.55 (s, 2H), 3.78-3.74 (m, 1H), 3.62-3.56 (m, 2H), 3.50 (s, 3H),3.44-3.32 (m, 1H), 2.52 and 2.42 (2 singlets, amide rotamers, ArCH₃,3H), 2.44 (s, 3H), 2.11-1.99 (m, 8H), 1.93-1.83 (m, 2H).

Compound 249.4-(1-(4-Cyclobutyl-5-(4,5-dimethyl-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 453 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.68(d, 2H), 7.51 (d, 2H), 7.31 (d, 1H), 7.32 and 7.30 (2 singlets, amiderotamers, ArH, 1H), 4.90-4.88 (m, 1H), 3.96-3.87 (m, 1H), 3.70-3.62 (m,1H), 3.32-3.29 (m, 1H), 3.02 (t, 2H), 2.44 and 2.33 (2 singlets, amiderotamers, ArCH₃, 3H), 2.20 (s, 6H), 2.18-1.90 (m, 7H), 1.88-1.78 (m,3H).

Compound 250.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 439 (M+H)⁺. ¹H NMR (100 MHz, CD₃OD): δ 7.68(d, 2H), 7.49-7.39 (m, 4H), 7.36 and 7.34 (2 singlets, amide rotamers,ArH, 1H), 4.90-4.86 (m, 1H), 3.75-3.70 (m, 1H), 3.63-3.55 (m, 1H),3.33-3.24 (m, 1H), 3.04-2.99 (m, 2H), 2.51 and 2.41 (2 singlets, amiderotamers, ArCH₃, 3H), 2.44 (s, 3H), 2.28-1.96 (m, 1.89-1.81 (m, 3H),1.77-1.74 (m, 1H).

Compound 251.4-(1-(4-Cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 493 (M+H)⁺.

Compound 252.4-(1-(5-(5-Chloro-1H-imidazol-2-yl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 459 (M+H)⁺.

Compound 253.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-1H-imidazole-5-carbonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 246.m/z (ES+) 450 (M+H)⁺.

Compound 254.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide.To a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoicacid (compound 234, 50 mg, 0.124 mmol) in DMF (2 mL) were added EDCI (36mg, 0.186 mmol), HOBt (10 mg, 0.5 mmol), diisopropylethyl amine (54 mg,0.434 mmol), and methyl amine (125 ul, 2.5 M in THF). The reactionmixture was stirred for 12 hours at room temperature and quenched withsaturated aqueous NaHCO₃ (50 mL). After extraction with ethyl acetate(2×50 mL), the combined organic layers were dried over Na₂SO₄, filtered,and concentrated in vacuo Purification via SiO₂ flash chromatographywith ethyl acetate to ethyl acetate/methanol=98/2 afforded5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(28.3 mg, 55% yield) as a white solid. m/z (ES+) 416 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆): δ 8.13 (q, J=4.5 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H),7.55-7.45 (m, 2H), 7.26 (br s, 1H), 7.12 & 6.99 (2 singlets, amiderotamers, Ar—H, 1H), 4.70 (br d, J=11.9 Hz, 1H), 3.86-3.72 (m, 1H),3.50-3.35 (m, 1H), 3.13 (t with fine structure, J=12.3 Hz, 1H),2.99-2.78 (m, 2H), 2.72 (d, J=4.6 Hz, 3H), 2.39-2.17 (m, 5H), 2.17-1.98(m, 2H), 1.98-1.81 (m, 2H), 1.81-1.35 (m, 4H).

Compound 255.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N-(2-methoxyethyl)-4-methylbenzamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(compound 254). m/z (ES+) 460 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27(t, 1H), 7.78 (d, 2H), 7.49 (d, 2H), 7.26 (s, 1H), 7.12 and 6.98 (2singlets, amide rotamers, 1H), 4.70 (d, 1H), 3.85-3.75 (m, 1H), 3.44 (t,3H), 3.39-3.33 (m, 2H), 3.30 (s, 3H), 3.19-3.03 (m, 1H), 3.02-2.71 (m,2H), 2.32 and 2.26 (2 singlets, amide rotamers, ArCH₃, 3H), 2.38-2.17(m, 2H), 2.15-2.00 (m, 2H), 1.98-1.81 (m, 2H), 1.83-1.47 (m, 4H).

Compound 256.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N-ethyl-4-methylbenzamide.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(compound 254). m/z (ES+) 430 (M+H)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21(t, 1H), 7.78 (d, 2H), 7.56-7.45 (m, 2H), 7.31-7.20 (m, 1H), 7.11 and6.98 (2 singlets, amide rotamers, 1H), 4.74-4.65 (m, 1H), 3.85-3.74 (m,1H), 3.50-3.37 (m, 1H), 3.22 (q, 2H), 3.20-3.05 (m, 2H), 2.32 and 2.22(2 singlets, amide rotamers, ArCH₃, 3H), 3.01-2.76 (m, 2H), 2.38-2.17(m, 2H), 2.18-1.97 (m, 2H), 1.98-1.84 (m, 2H), 1.81-1.38 (m, 3H), 1.10(t, 3H).

Compound 257.1. (S)-Tetrahydrofuran-2-carbonyl chloride. To around-bottom flask was added a solution of(S)-tetrahydrofuran-2-carboxylic acid (4.64 g, 40.0 mmol, 1.00 equiv) indichloromethane (25 mL). N,N-dimethylformamide (0.05 mL, 0.05 equiv) and(COCl)₂ (5.2 mL, 1.50 equiv) were added dropwise to the reaction. Theresulting solution was stirred for 1 h at 25° C., then concentrated invacuo to yield 5.00 g (93%) of (S)-tetrahydrofuran-2-carbonyl chlorideas a yellow oil.

Compound 257.2. (S)-2-Bromo-1-(tetrahydrofuran-2-yl)ethanone. To a250-mL three neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was added a solution of(diazomethyl)trimethylsilane (20 mL, 2 M in hexane) in ether (150 mL). Asolution of (S)-tetrahydrofuran-2-carbonyl chloride (compound 257.1,5.00 g, 37.2 mmol, 1.00 equiv) in ether/DCM (25/10 mL) was addeddropwise at 0° C. and stirred for 20 min at 0° C. Hydrogen bromide (48%)(8 mL, 1.50 equiv) was added dropwise. The resulting solution wasstirred for 30 min at 10° C., then washed with 2×100 mL of water and1×50 mL of brine. The mixture was dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:50) aseluent to furnish 2.50 g (35%) of(S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone as a yellow oil.

Compound 257.3. (S)-Methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate. To around-bottom flask was added a solution of methyl5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 1.30g) in CH₃CN (30 mL). (S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone(compound 257.2, 1.92 g, 9.95 mmol) and potassium carbonate (4.20 g,30.4 mmol) were added to the reaction. The resulting solution wasstirred for 3 days at 75° C. under nitrogen. After cooling to ambienttemperature, the solids were removed by filtration. The filtrate wasconcentrated in vacuo and diluted with 30 mL of H₂O. The aqueous phasewas extracted with 3×50 mL of ethyl acetate and the combined organiclayers were dried over anhydrous sodium sulfate, then concentrated invacuo. The mixture was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (1:2) as eluent to yield 400 mg (25%)of (S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as alight yellow solid.

Compound 257.4.(S)-2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoicacid. To a round-bottom flask was added a solution of (S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate(compound 257.3, 400 mg, 1.33 mmol, 1.00 equiv) and sodium hydroxide(300 mg, 7.50 mmol, 5.63 equiv) in a solvent mixture of methanol and H₂O(20/10 mL). The resulting solution was stirred for 2 h at 70° C. Aftercooling to ambient temperature, the organic solvent was removed underreduced pressure. The residual aqueous layer was washed with 2×50 mL ofethyl acetate. The pH of the aqueous layer was adjusted to 5-6 withhydrogen chloride (aq., 6 M), then extracted with 3×50 mL of ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated in vacuo. This resulted in 340 mg (90%) of(S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as ayellow solid.

Compound 257.(S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of (S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate(compound 257.4, 143 mg, 0.500 mmol, 1.00 equiv) inN,N-dimethylformamide (10 mL), HBTU (285 mg, 0.750 mmol, 1.50 equiv) wasadded to the reaction, and it was stirred for 30 min at 25° C. To thiswas added 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,133 mg, 0.600 mmol, 1.20 equiv) and DIEA (390 mg, 3.02 mmol, 6.04 equiv)dropwise. The resulting solution was stirred for 30 min at 25° C., thenquenched with 20 mL of water. The mixture was extracted with 3×25 mL ofethyl acetate and the combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with methanol/ethyl acetate (1:30) aseluent. The product (˜100 mg) was further purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, Xbridge PrepC18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH₃H₂O and CH₃CN(35% CH₃CN up to 52% in 8 min, up to 100% in 1 min, down to 35% in 1min); Detector, Waters 2489 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 34.6 mg (15%) of thetitle compound as a white solid. m/z (ES+) 455 (M+H)⁻.

Compound 258.1.5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid. Thetitle compound was synthesized using standard chemical manipulations andprocedures similar to those used for the preparation of compound 152.8using 4-fluoro-2-methylbenzoic acid instead of 4-bromo-2-methylbenzoicacid and propionohydrazide instead of acetohydrazide.

Compound 258.2.4-(1-(5-(5-Ethyl-4H-14-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid(compound 258.1, 125 mg, 0.500 mmol, 1.00 equiv) in DMF (10 mL). EDC.HCl(143 mg, 0.750 mmol, 1.50 equiv), 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 122 mg, 0.550 mmol, 1.10 equiv), and4-dimethylaminopyridine (183 mg, 1.50 mmol, 3.00 equiv) were added inportions. The resulting solution was stirred for 1 h at 40° C. in an oilbath, then quenched with 50 mL of NH₄Cl (aq. sat.). The mixture wasextracted with 40 mL of ethyl acetate and the combined organic layerswere washed with 3×30 mL of NH₄Cl (aq. sat.), dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 180 mg(86%) of4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrileas a white solid.

Compound 258.4-(1-4-(Azetidin-1-yl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a 10-mL sealed tube was added a solution of4-(1-[[5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylphenyl]carbonyl]piperidin-4-yl)benzonitrile(compound 258.2, 83.5 mg, 0.200 mmol, 1.00 equiv) in 1,4-dioxane (5 mL).Azetidine hydrochloride (93.0 mg, 0.990 mmol, 5.00 equiv) was added tothe reaction in portions. Potassium carbonate (276 mg, 2.00 mmol, 10.0equiv) was also added to the above mixture. The resulting solution wasstirred overnight at 105° C. behind a blast shield, then cooled to rt.The reaction was quenched with 20 mL of water. The mixture was extractedwith 30 mL of ethyl acetate and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theproduct (80 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18,19*150 mm 5 um; mobile phase, water with 50 mL NH₄CO₃ and CH₃CN (41.0%CH₃CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 41.0% in 2min); Detector, Waters 2489 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 18.0 mg (20%) of thetitle compound as a white solid. m/z (ES+) 455 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.68 (d, J=6.3 Hz, 2H), 7.48 (d, J=5.7 Hz, 2H), 7.24 & 7.13 (2singlets, amide rotamers, Ar—H, 1H), 6.52 (s, 1H), 4.91-7.77 (m, 1Hpartially obscured by water peak), 3.81-3.67 (m, 1H), 3.68 (t, J=5.6 Hz,4H), 3.32-3.18 (m, 1H), 3.05-1.91 (m, 2H), 2.84 (q, J=5.8 Hz, 2H),2.45-2.19 (m, 5H), 2.09-1.91 (m, 1H), 1.91-1.49 (m, 3H), 1.39 (t, J=5.7Hz, 3H).

Compound 259.4-(1-(5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-2-methyl-4-(methylthio)benzoyl)piperidin-4-yl)benzonitrile.To a round-bottom flask was added a solution of4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 258.2, 20 mg, 0.050 mmol, 1.0 equiv) in N,N-dimethylformamide(3 mL). Sodium thiomethoxide (70 mg, 0.10 mmol, 2.0 equiv) was added tothe reaction. The resulting mixture was stirred for 15 h at 110° C. inan oil bath, and then cooled to ambient temperature and quenched with100 mL of ice water. The mixture was extracted with 50 mL of ethylacetate and the combined organic layers were washed with 2×50 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The product (50 mg) was further purified by Prep-HPLCwith the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column,SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA andCH₃CN (37% CH₃CN up to 49% in 7 min, up to 100% in 3 min, down to 37% in2 min); Detector, Waters 2489 254 & 220 nm. The fractions containingpure compound were combined and lyophilized to yield 4 mg (19%) of thetitle compound as a white solid. m/z (ES+) 446 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.69 (d, J=8.4 Hz, 2H), 7.61-7.43 (m, 3H), 7.35 (br s, 1H),˜4.85 (1H partially obscured by water peak), 3.77-3.60 (m, 1H), ˜3.3 (1Hpartially obscured by methanol solvent peak), 3.08-2.94 (m, 2H), 2.91(q, J=7.7 Hz, 2H), 2.51 (s, 3H), 2.47 & 2.37 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.10-1.97 (m, 1H), 1.88-1.55 (m, 3H), 1.40 (t,3H).

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compound5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(compound 254):

Cmpnd m/z +190 Compound Name Compound Structure (ES+) 260 5-(4-(4-methoxyphenyl) piperidine-1- carbonyl)-2- methyl-N-(6- (pyrrolidin-1-yl)pyridin-3- yl)benzamide

499 (M + H)⁺ 261 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2-methyl-N- ((tetrahydrofuran- 2-yl)methyl) benzamide

432 (M + H)⁺ 262 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2-methyl-N- (tetrahydrofuran-3- yl)benzamide

418 (M + H)⁺ 263 3-(4-(4- cyanophenyl) piperidine-1- carbonyl)-N-(6-(pyrrolidin-1- yl)pyridin-3- yl)benzamide

480 (M + H)⁺ 264 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2-methyl-N- (piperidin-4- ylmethyl) benzamide

445 (M + H)⁺ 265 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2-methyl-N-((1- methylpiperidin- 4-yl)methyl) benzamide

459 (M + H)⁺ 266 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2-methyl-N- ((tetrahydrofuran- 3-yl)methyl) benzamide

432 (M + H)⁺ 267 2-methyl-5-(4- (pyridin-4- yl)piperidine-1-carbonyl)-N-(6- (pyrrolidin-1- yl)pyridin-3- yl)benzamide

470 (M + H)⁺ 268 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-N-(6-((2- hydroxyethyl) (methyl)amino) pyridin-3-yl)-2- methylbenzamide

499 (M + H)⁺ 269 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)- N-(6-(3-hydroxyazetidin-1- yl)pyridin-3-yl)-2- methylbenzamide

497 (M + H)⁺ 270 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2-methyl-N-(6-(4- methylpiperazin-1- yl)pyridin-3- yl)benzamide

524 (M + H)⁺

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 27,38, and 211:

Preparation similar to Cmpnd Compound compound #(s) # Name CompoundStructure [m/z (ES+)] 271 4-(1-(4-methyl- 3-(6-(4- methylpiperazin-1-yl)-3H- imidazo[4,5- c]pyridin-2- yl)benzoyl) piperidin-4-yl)benzonitrile

27 [520 (M + H)⁺] 272 4-(1-(3-(6-(3- hydroxyazetidin- 1-yl)-3H-imidazo[4,5- c]pyridin-2-yl)- 4-methylbenzoyl) piperidin-4-yl)benzonitrile

27 [493 (M + H)⁺] 273 4-(1-(3-(6-((2- hydroxyethyl) (methyl)amino)-3H-imidazo[4,5- c]pyridin-2-yl)- 4-methylbenzoyl) piperidin-4-yl)benzonitrile

27 [495 (M + H)⁺] 274 4-(1-(3-(5- isopropyl-4H- 1,2,4-triazol-3- yl)-4-methylbenzoyl) piperidin-4- yl)benzonitrile

38 [414 (M + H)⁺] 275 4-(1-(3-(5- ethyl-4H-1,2,4- triazol-3-yl)-4-methylbenzoyl) piperidin-4- yl)benzonitrile

38 [400 (M + H)⁺] 276 (S)-4-(1-(4- methyl-3-(5- ((tetrahydrofuran-3-yl)amino)- 4H-1,2,4-triazol-3- yl)benzoyl) piperidin-4-yl)benzonitrile

211 [457 (M + H)⁺] 277 (R)-4-(1-(4- methyl-3-(5- ((tetrahydrofuran-3-yl)amino)-4H-1,2,4- triazol-3- yl)benzoyl) piperidin-4- yl)benzonitrile

211 [457 (M + H)⁺] 278 (R)-4-(4-fluoro- 1-(4-methyl-3-(5-((tetrahydrofuran- 3-yl)amino)- 4H-1,2,4-triazol-3- yl)benzoyl)piperidin-4- yl)benzonitrile

211 [475 (M + H)⁺] 279 4-(1-(2,4- dimethyl-5-(5- ((tetrahydrofuran-3-yl)amino)- 4H-1,2,4-triazol-3- yl)benzoyl)piperidin- 4-yl)benzonitrile

211 [471 (M + H)⁺]

Compound 280.1.N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-isonicotinoylhydrazinecarboxamide.A solution of 4-(1-(3-Amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 121.1, 0.1 g. 0.31 mmol) and triethyl amine (0.09 ml, 0.62mmol) in DCM (5 ml) was added to a solution of phosgene (20% in toluene.0.31 ml, 0.62. mmol) in DCM (5 ml) at 0° C. After the resulting reactionmixture was stirred at room temperature for 1.5 hours, all solvents wereremoved under reduced pressure. The residue was dried under high-vacuumfor 30 minutes then was re-dissolved in EtOH (5 ml).Isonicotinohydrazide (0.05 g, 0.34 mmol) was added. The mixture washeated at 80° C. over night. The ethanol was removed and the residue waspurified using prep.-TLC (10% MeOH in DCM) to give the product as alight brown solid. Yield: 0.14 g, 93%. m/z (ES+) 483.2 (M+H)⁺.

Compound 280. 4-(1-(4-Methyl-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile. To asolution ofN-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-isonicotinoylhydrazinecarboxamide(compound 280.1, 0.14 g, 0.29 mmol) and PPh₃ (0.09 g, 0.35 mmol) in DCM(10 ml) was added triethyl amine (0.061 ml, 0.43 mmol) followed withCCl₄ (0.08 ml, 0.87 mmol). The mixture was refluxed for 3 hours. TLC andLCMS showed that the reaction was complete. The mixture was cooled toroom temperature, diluted with DCM (100 ml), and washed with water (20ml). The organic layer was dried with Na₂SO₄, concentrated and purifiedusing prep.-TLC (5% MeOH in CH₂Cl₂) to yield 54 mg (42%) of a whitesolid. m/z (ES+) 465.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (br,1H), 8.77 (d, 2H), 7.92 (s, 1H), 7.81-7.73 (m, 4H), 7.50 (d, 2H), 7.33(d, 1H), 7.14 (d, 1H), 4.64 (m, 1H), 3.81 (m, 1H), 3.17 (m, 1H),3.00-2.80 (m, 2H), 2.35(s, 3H), 1.95-1.57 (m, 4H).

Compound 281.1.N-(5-(4-4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-1-carbothioamide.To a solution of4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (121.1, 0.1 g,0.32 mmol) in DMF (3 ml) was added 1,1′-thio-CDI (0.056 g, 0.32 mmol).The mixture was stirred at room temperature for 3 hours. LCMS showed thereaction was complete. The mixture was carried to the next step in onepot without work up or purification. m/z (ES+) 430 (M+H)⁺.

Compound 281.2.1-(4-Aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)thiourea.To a solution ofN-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-1-carbothioamide(281.1) in DMF continued from the prior step was addedpyridine-3,4-diamine (0.034, 0.32 mmol). The mixture was stirred at roomtemperature for 3 hours. LCMS showed the reaction was complete. Thereaction was carried to the next step without workup or purification.m/z (ES+) 471 (M+H)⁺.

Compound 281.4-(1-(3-((1H-Imidazo[4,5-c]pyridin-2-yl)amino)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.To a solution of1-(4-aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)thiourea(281.2) in DMF continued from the prior step was added EDCI (0.12 g,0.64 mmol). The mixture was stirred at room temperature overnight. TheDMF was removed under high vacuum and the residue was purified usingprep.-TLC (5% MeOH in EtOAc) to yield 76 mg (56% for 3 steps) of a whitepowder. (ES+) 437 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (br, 1H),8.48 (s, 1H), 8.40 (s, 1H), 8.08 (d, 1H), 7.78 (d, 2H), 7.53 (d, 2H),7.29 (d, 2H), 7.05 (d, 1H), 4.65 (m, 1H), 3.91 (m, 1H), 3.17 (m, 1H),3.04-3.72 (m, 2H), 2.36 (s, 3H), 1.97-1.60 (m, 4H).

Compound 282.1.N-((5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)carbamothioyl)isobutyramide.Into around-bottom flask, was placed a solution of NH₄SCN (72 mg, 0.95mmol, 2.00 equiv) in acetone (10 mL). A solution of 2-methylpropanoylchloride (50 mg, 0.47 mmol, 1.00 equiv) in acetone was added (5 mL)dropwise at 25° C. and the reaction was stirred overnight at 40° C. inan oil bath. To this was added4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound121.1, 150 mg, 0.42 mmol, 1.00 equiv) at 25° C. The resulting solutionwas stirred for 2 h at 25° C., then concentrated under reduced pressure.The residue was diluted with 100 mL of ethyl acetate. The organic layerwas washed with 2×30 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with dichloromethane/methanol (20:1) aseluent to furnish 150 mg (64%) of the title compound as a brown oil.

Compound 282.4-(1-(34(5-Isopropyl-4H-1,2,4-triazol.-3-yl)amino)-4-methylbenzoyl)piperidin-4-yl)benzonitrile.Into a 10-mL sealed tube, was placed a solution ofN-((5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)carbamothioyl)isobutyramide(compound 282.1, 200 mg, 0,40 mmol, 1.00 equiv, 90%) in ethanol (3 mL).NH₂NH₂HCl (234 mg, 2.23 mmol, 5.00 equiv) and potassium carbonate (185mg, 1.34 mmol, 3.00 equiv) were added to the reaction. The resultingsolution was stirred overnight at 80° C. in an oil bath behind a blastshield. After cooling to ambient temperature, the mixture wasconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and water. The organic phase was washed with brine, dried(Na₂SO₄), and concentrated. The crude product (˜50 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-006 (Waters)):Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with0.05% TFA and CH₃CN (hold 5.0% CH₃CN in 2 min, up to 30.0% in 1 min, upto 60.0% in 12 min, up to 100.0% in 1 min); Detector, UV 254/220 nm. Thefractions containing pure compound were combined and lyophilized toyield 10.3 mg (6%) of the title compound as a white solid. m/z (ES+) 429(M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 280,121, 281, and 282:

Preparation similar to Cmpnd Compound compound #(s) # Name CompoundStructure [m/z (ES+)] 283 4-(1-(4-methyl- 3-((5-(pyridin-3-yl)-1,3,4-oxadiazol- 2-yl)amino)benzoyl) piperidin-4- yl)benzonitrile

280 [465 (M + H)⁺] 284 4-(1-(3-((5- ethyl-1,3,4- oxadiazol-2-yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile

280 [416 (M + H)⁺] 285 4-(1-(3-((1H- imidazo[4,5- b]pyridin-2-yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile

281 [437 (M + H)⁺] 286 4-(1-(3-((1H- imidazol-2- yl)amino)-4-methylbenzoyl) piperidin-4- yl)benzonitrile

281 [386 (M + H)⁺] 287 4-(1-(3-((5- (dimethylamino)- 1H-imidazo[4,5-b]pyridin-2- yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile

281 [480 (M + H)⁺] 288 4-(1-(3-((5- (isobutylamino)- 1H-imidazo[4,5-b]pyridin-2- yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile

281 [508 (M + H)⁺] 289 4-(1-(3-((5- (isopropylamino)- 1H-imidazo[4,5-b]pyridin-2- yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile

281 [494 (M + H)⁺] 290 5-((5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylphenyl) amino)-N- isopropyl- nicotinamide

121 [482 (M + H)⁺] 291 2-((5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylphenyl) amino)-N- cyclopropyl- isonicotinamide

121 [480 (M + H)⁺] 292 6-((5-(4-(4- cyanophenyl) pipridine-1-carbonyl)-2- methylphenyl) amino)-N- cyclopropyl- nicotinamide

121 [480 (M + H)⁺] 293 2-((5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylphenyl) amino)-N- ethyl- isonicotinamide

121 [468 (M + H)⁺] 294 6-((5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylphenyl) amino)-N- ethylnicotinamide

121 [468 (M + H)⁺] 295 4-(1-(4-methyl- 3-((4-(4- methylpiperazine-1-carbonyl)pyridin-2- yl)amino)benzoyl) piperidin-4- yl)benzonitrile

121 [523 (M + H)⁺] 296 4-(1-(3-((5- ethyl-4H-1,2,4- triazol-3-yl)amino)-4-methylbenzoyl) piperidin-4- yl)benzonitrile

282 [415 (M + H)⁺]

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 26,43, 48, 50, 51, 64, and 80:

Preparation similar to Cmpnd compound #(s) # Compound Name CompoundStructure [m/z (ES+)] 297 1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2- methylphenyl)-3- isobutylurea

64 [437 (M + H)⁺] 298 N-(5-(4-(5- cyanopyridin-2- yl)piperidine-1-carbonyl)-2- methylphenyl) pyrrolidine-1- carboxamide

50 and 64 [418 (M + H)⁺] 299 N-(5-(4-(6- cyanopyridin-3-yl)piperidine-1- carbonyl)-2- methylphenyl) pyrrolidine-1- carboxamide

51 and 64 [418 (M + H)⁺] 300 1-(5-(4-(6- cyanopyridin-3-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- (2-methoxyethyl)urea

51 and 64 [422 (M + H)⁺] 301 1-(5-(4-(5- cyanopyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- (2-methoxyethyl)urea

50 and 64 [422 (M + H)⁺] 302 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)pyridazin- 3-yl)-3-(2- methoxyethyl)urea

64 [409 (M + H)⁺] 303 N-(5-(4-(5- cyanopyridin-2- yl)piperidine-1-carbonyl)-2- methylphenyl)-6- (ethylamino) nicotinamide

50 [469 (M + H)⁺] 304 6-(azetidin-1-yl)- N-(5-(4-(5- cyanopyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl) nicotinamide

50 [481 (M + H)⁺] 305 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)pyridazin- 3-yl)-3-isobutylurea

64 [407 (M + H)⁺] 306 1-(5-(4-(5- cyanopyridin-2- yl)piperidine-1-carbonyl)-2- methylphenyl)-3- isopropylurea

50 and 64 [406 (M + H)⁺] 307 1-(5-(4-(5- cyanopyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- cyclobutylurea

50 and 64 [418 (M + H)⁺] 308 1-(5-(4-(5- cyanopyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- cyclopentylurea

50 and 64 [432 (M + H)⁺] 309 1-(5-(4-(5- cyanopyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- (oxetan-3-yl)urea

50 and 64 [420 (M + H)⁺] 310 1-(5-(4-(5- cyanopyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- (tetrahydro-2H-pyran-4-yl)urea

50 and 64 [448 (M + H)⁺] 311 1-(5-(4-(5- cyanopyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- (tetrahydro-2H-pyran-3-yl)urea

50 and 64 [448 (M + H)⁺] 312 6-(azetidin-1-yl)- N-(5-(4-(4-cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2- methylphenyl)nicotinamide _

43 [498 (M + H)⁺] 313 1-(5-(4-(5- cyanopyridin-2- yl)piperidine-1-carbonyl)-2- methylphenyl)-3- (tetrahydrofuran- 3-yl)urea

50 and 64 [434 (M + H)⁺] 314 2-(azetidin-1-yl)- N-(5-(4-(4-cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2- methylphenyl)pyrimidine-5- carboxamide

43 [499 (M + H)⁺] 315 1-(5-(4-(5- cyanopyridin-2- yl)-4-fluoropiperidine- 1-carbonyl)-2- methylphenyl)-3- (tetrahydrofuran-3-yl)urea

26 and 64 [452 (M + H)⁺] 316 (S)-1-(5-(4-(5- cyanopyridin-2- yl)-4-fluoropiperidine- 1-carbonyl)-2- methylphenyl)-3- (tetrahydrofuran-3-yl)urea

26 and 64 [452 (M + H)⁺] 317 1-(5-(4-(5- cyanopyridin-2- yl)-4-fluoropiperidine- 1-carbonyl)-2- methylphenyl)-3- (tetrahydro-2H-pyran-4-yl)urea

26 and 64 [466 (M + H)⁺] 318 1-(5-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2- methylphenyl)-3- (tetrahydrofuran-3-yl)urea

64 [451 (M + H)⁺] 319 (S)-1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2- methylphenyl)-3- (tetrahydrofuran- 3-yl)urea

64 [451 (M + H)⁺] 320 1-(5-(4-(5- cyanopyridin-2- yl)-4-fluoropiperidine- 1-carbonyl)-2- methylphenyl)-3- (oxetan-3-yl)urea

26 and 64 [438 (M + H)⁺] 321 1-(2-chloro-5-(4- (4-cyanophenyl)-4-fluoropiperidine- 1-carbonyl)phenyl)- 3-(tetrahydrofuran- 3-yl)urea

26 and 64 [471 (M + H)⁺] 322 6-(azetidin-1-yl)- N-(5-(4-(5-cyanopyridin-2- yl)-4- fluoropiperidine- 1-carbonyl)-2- methylphenyl)nicotinamide

26 and 43 [499 (M + H)⁺] 323 N-(5-(4-(5- cyanopyridin-2- yl)-4-fluoropiperidine- 1-carbonyl)-2- methylphenyl)-6- (isopropylamino)nicotinamide

26 and 43 [501 (M + H)⁺] 324 1-(5-(4-fluoro-4- (5-methoxypyridin-2-yl)piperidine-1- carbonyl)-2- methylphenyl)-3- (tetrahydrofuran-3-yl)urea

1, 11, and 64 [457 (M + H)⁺] 325 1-(5-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2- methylphenyl)-3- ((1-methylpiperidin-4-yl)methyl)urea

64 [492 (M + H)⁺] 326 6-(azetidin-1-yl)- N-(2-methyl-5-(4- (pyridin-4-yl)piperidine-1- carbonyl)phenyl) nicotinamide

43 [492 (M + H)⁺] 327 1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2- methylphenyl)-3- (piperidin-4- ylmethyl)urea

64 [492 (M + H)⁺] 328 6-(azetidin-1-yl)- N-(5-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2- fluorophenyl) nicotinamide

43 [502 (M + H)⁺] 329 3-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2- methylphenyl)-1- (2-methoxyethyl)- 1-methylurea

64 [453 (M + H)⁺] 330 6-(azetidin-1-yl)- N-(5-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2- (trifluoromethyl) phenyl)nicatinamide

43 [552 (M + H)⁺] 331 6-(azetidin-1-yl)- N-(5-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2- methoxyphenyl) nicotinamide

43 [514 (M + H)⁺] 332 (S)-1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2- methylphenyl)-3- ((tetrahydrofuran- 2-yl)methyl)urea

64 [465 (M + H)⁺] 333 (R)-1-(2-chloro- 5-(4-(4- cyanophenyl)-4-fluoropiperidine-1- carbonyl)phenyl)-3- (tetrahydrofuran- 3-yl)urea

64 [471 (M + H)⁺] 334 N-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2,4- dimethylphenyl)- 6-(piperazin-1- yl)nicotinamide

43 [541 (M + H)⁺] 335 (R)-1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2- ethyl-4- methylphenyl)-3- (tetrahydrofuran- 3-yl)urea

64 [479 (M + H)⁺] 336 (R)-tetrahydrofuran- 3-yl (3-(4-(4-cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-4- methylphenyl) carbamate

80 [452 (M + H)⁺] 337 1-acetylpyrrolidin- 3-yl (3-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-4- methylphenyl) carbamate

80 [493 (M + H)⁺] 338 (R)-1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-2-ethyl- 4-methylphenyl)-3- ((tetrahydrofuran-2-yl)methyl)urea

64 [493 (M + H)⁺] 339 (S)-tetrahydrofuran- 3-yl (5-(4-(4-cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2- methylphenyl) carbamate

80 [452 (M + H)⁺] 340 6-(azetidin-1-yl)- N-(5-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2- ethyl-4- methylphenyl) nicotinamide

43 [526 (M + H)⁺] 341 N-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-1-carbonyl)-4-ethyl- 2-methylphenyl)-6- ((2-methoxyethyl) (methyl)amino)nicotinamide

43 and 48 [558 (M + H)⁺] 342 N-(5-(4-(4- cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2-ethyl- 4-methylphenyl)-6-(isopropylamino) nicotinamide

43 [528 (M + H)⁺] 343 N-(5-(4-(5- cyanopyridin-2-yl)-4-fluoropiperidine- 1-carbonyl)-2,4- dimethylphenyl)-6- morpholino-nicotinamide

26 and 43 [543 (M + H)⁺] 344 (R)-tetrahydrofuran- 3-yl (5-(4-(4-cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-4-ethyl-2- methylphenyl)carbamate

48 and 80 [480 (M + H)⁺] 345 (S)-tetrahydrofuran- 3-yl (5-(4-(4-cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-4-ethyl-2- methylphenyl)carbamate

48 and 80 [480 (M + H)⁺]

Compound 346.1. 2-(1-Benzyl-4-hydroxypiperidin-4-yl)-5-bromobenzoicacid. To a stirred solution of 2,5-dibromobenzoic acid (27.8 g, 100mmol, 1.00 equiv) in THF/Et₂O (450/50 mL) under nitrogen at −78° C. wasadded dropwise n-BuLi (2.5M) (88 mL, 2.20 equiv). After 2 h at −78° C.,was added 1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equiv). Theresulting solution was stirred for 0.5 h at −78° C. and then warmed toroom temperature, and stirred overnight. The reaction was quenched bycarefully adding 200 mL of water. The pH of the mixture was adjusted to2-3 with hydrogen chloride (aq., 2 M). The aqueous phase was extractedwith 3×500 mL of ethyl acetate and 3×500 mL of tetrahydrofuran. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 38.9 g (crude) of the titlecompound as a yellow solid.

Compound 346.2.1′-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one. Into around-bottom flask, was placed a solution of crude compound 346.1 (38.9g, 100 mmol, 1.00 equiv) in tetrahydrofuran (800 mL). To this was addedsulfuric acid (8 mL) dropwise. The resulting solution was stirredovernight at reflux in an oil bath. The pH value of the solution wasslowly adjusted to 10 with LiOH (aq. sat.). The aqueous phase wasextracted with 3×500 mL of ethyl acetate and the combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:8-1:5) as eluent to furnish 8.00 g(22%) of the title compound as a white solid.

Compound 346.3.1′-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4′-piperidine]. To a solutionof compound 346.2 (10.0 g, 26.9 mmol, 1.00 equiv) in tetrahydrofuran(150 mL) under nitrogen at −10° C. was added dropwise BH₃-THF (135 mL,5.00 equiv). The resulting solution was stirred for 30 min at roomtemperature and then heated at reflux temperature overnight. Aftercooling to −10° C., hydrogen chloride (aq., 6 M, 60 mL) was addeddropwise at −10° C. The resulting solution was heated to reflux for 5 hin an oil bath. The reaction mixture was cooled and the pH of thesolution was adjusted to 10 with potassium hydroxide (aq., 1 M). Theaqueous phase was extracted with 2×200 mL of ethyl acetate and thecombined organic layers were washed with 2×300 mL of brine, dried oversodium sulfate, and concentrated under reduced pressure to yield 15.0 g(crude) of the tile compound as a yellow oil.

Compound 346.4.1′-Benzyl-3H-spiro[isobenzofuran-1,4′-piperidine]-5-carbonitrile. Into athree neck round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was placed a solution of compound 346.3(12.0 g, 33.6 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL).Zn(CN)₂ (4.50 g, 38.5 mmol, 1.14 equiv) and Pd(PPh₃)₄ (4.00 g) wereadded to the reaction. The resulting solution was stirred overnight at90° C. in an oil bath. The reaction mixture was cooled to rt, thenquenched with 200 mL of FeSO₄ (aq. sat.) and diluted with ethyl acetate.The resulting mixture was stirred vigorously then filtered throughcelite and washed with 1 M FeSO₄, water, and ethyl acetate. The layerswere separated and the aqueous phase was extracted with 2×200 mL ofethyl acetate. The combined organic layers were washed with 2×100 mL ofsodium chloride (aq. sat.), dried over sodium sulfate, and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with petroleum ether/ethyl acetate (10:1˜5:1.) as eluentto yield 9.12. g (89%) of the title compound as a yellow oil.

Compound 346.5. 3H-Spiro[isobenzofuran-1,4′-piperidine]-5-carbonitrile.To a solution of 346.4 (9.12 g, 30.0 mmol, 1.00 equiv) in DCE (150 mL)0° C. was added dropwise 1-chloroethyl chloroformate (8.52 g, 60.0 mmol,2.00 equiv). After stirring at ambient temperature for 30 min,triethylamine (9.09 g, 3.00 equiv) was carefully added to the mixture.The resulting solution was heated to reflux for 2 h in an oil bath, thenconcentrated under reduced pressure. The residue was dissolved in 100 mLof methanol and then heated to reflux for 1 h in an oil bath. Theresulting mixture was concentrated under reduced pressure and theresidue was taken up in water (100 mL). The pH of the mixture wasadjusted to 10 with sodium hydroxide (aqueous, 1 M). The aqueous phasewas extracted with 3×200 mL of ethyl acetate and the combined organiclayers were washed with 2×100 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/methanol (100:0 to 3:1) as eluent to furnish 3.50 g (46%) of thetitle compound as a yellow solid.

Compound 346.N-(5-(5-Cyano-3H-spiro[isobenzofuran-1,4′-piperidin]-1′-ylcarbonyl)-2-methylphenyl)-6-(pyrrolidin-1-yl)nicotinamide.The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compound 346.5 was in placeof compound 11.2. m/z (ES+) 522 (M+H)⁺.

Compound 347.1. tert-Butyl4-(4-cyanophenyl)-2-oxopiperidine-1-carboxylate. Into a round-bottomflask, was placed a solution of tert-butyl4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.4, 515 mg, 1.80mmol, 1.00 equiv) in ethyl acetate (5 mL). A solution of NaIO₄ (963 mg,4.50 mmol, 2.50 equiv) in water (5 mL) and RuCl₃ (74.7 mg, 0.36 mmol,0.20 equiv) was carefully added. The resulting mixture was stirredovernight at room temperature. The solids were removed by filtration andthe filtrate was washed with 2×20 mL of water, dried over anhydroussodium sulfate, and concentrated under reduced pressure to yield 432 mg(80%) of the title compound as a light yellow oil.

Compound 347.2, 4-(2-Oxopiperidin-4-yl)benzonitrile. Into a round-bottomflask, was placed a solution of compound 347.1 (432 mg, 1.44 mmol, 1.00equiv) in ethyl acetate (10 mL). Hydrogen chloride gas was bubbledthrough the solution and the resulting mixture was stirred for 0.5 h atroom temperature. The solids were collected by filtration, thendissolved in 50 mL of ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure toyield 254 mg (88%) of the title compound as a white solid.

Compound 347.3.4-(6-Methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile. Into around-bottom flask, was placed a solution of4-(2-oxopiperidin-4-yl)benzonitrile (347.2, 220 mg, 1.10 mmol, 1.00equiv) in dichloromethane (10 mL). Trimethyloxonium tetrafluoroborate(244.2 mg, 1.65 mmol, 1.50 equiv) was slowly added and the resultingmixture was stirred for 2 h at room temperature. The pH was carefullyadjusted to 8 with sodium bicarbonate (aq.). The organic layer waswashed with 2×20 mL of H₂O, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 212 mg (90%) of the titlecompound as a white solid.

Compound 347.4, 3-Amino-4-methylbenzohydrazide. Into a round-bottomflask, was placed a solution of methyl 3-amino-4-methylbenzoate (6.60 g,40.0 mmol, 1.00 equiv) in ethanol (100 mL). Hydrazine hydrate (10.0 g,200 mmol, 5.00 equiv) was added to the reaction. The resulting solutionwas stirred for 2 h at 100° C. in an oil bath. After cooling to ambienttemperature, the mixture was concentrated under reduced pressure. Theresidue was partitioned between water and ethyl acetate (20 mL). Theaquoeoues layer was extracted with 4×20 mL of ethyl acetate and thecombined organic layers were dried over anhydrous sodium sulfate,concentrated under reduced pressure, and dried under high-vacuum toyield 4.60 g (70%) of the title compound as a brown solid.

Compound 347.5.4-(3-(3-Amino-4-methylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile.To a solution of4-(6-methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile (compound347.3, 5.00 g, 23.36 mmol, 1.00 equiv) in 1,2-dichlorobenzene (100 mL)was added 3-amino-4-methylbenzohydrazide (compound 347.4, 4.63 g, 28.0mmol, 1.20 equiv). The resulting solution was stirred overnight at 150°C. in an oil bath. After cooling to ambient temperature, the resultingmixture was purified using silica gel column chromatography withdichloromethane/methanol (1:0˜100:1) as eluent to furnish 2.40 g (31%)of the title compound as a white solid.

Compound 347.N-(5-(7-(4-Cyanophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylphenyl)-6-(isopropylamino)nicatinamide.The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compound 347.5 was in placeof compound 42.2. m/z (ES+) 492 (M+H)⁺.

Compound 348.1. 2-Hydroxy-6-methyl-5-nitronicotinic acid, To a solutionof 2-hydroxy-6-methylnicotinic acid (14.0 g, 91.5 mmol, 1.00 equiv) insulfuric acid (conc.) (140 mL) at 0° C. was added dropwise a solution ofHNO₃ (12.0 g, 190 mmol, 2.00 equiv) in sulfuric acid (conc.) (10 mL).The resulting mixture was then stirred for 2 h at 90° C., cooled toambient temperature, and then quenched with 250 mL of ice water. Theresulting solids were collected by filtration and dried in an oven underreduced pressure to yield 15.8 g (87%) of the title compound as a yellowsolid.

Compound 348.2. Methyl 2-chloro-6-methyl-5-nitronicotinate. To asolution of 2-hydroxy-6-methyl-5-nitronicotinic acid (compound 348.1,15.0 g, 75.8 mmol, 1.00 equiv) in chlorobenzene (150 mL) were carefullyadded phosphoryl trichloride (45.0 g, 296 mmol, 4.00 equiv) andN,N-dimethylformamide (1.5 mL, 0.10 equiv). The resulting mixture wasstirred for 2 h at 135° C., and then concentrated under reducedpressure. The residue was dissolved in 20 mL of DCM. To this was addedmethanol (20 mL) dropwise. The resulting solution was stirred for 3 h at25° C., and then concentrated under reduced pressure. To the residue wascarefully added 100 mL of water and the pH of the resulting mixture wasslowly adjusted to 8 with sodium bicarbonate (aq.). The aqueous phasewas extracted with 2×200 mL of ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure to yield 17.6 g (crude) of the title compound as ayellow solid.

Compound 348.3. Methyl 5-amino-6-methylnicotinate. A round-bottom flask,containing a solution of methyl 2-chloro-6-methyl-5-nitronicotinate(12.8 g, 55.5 mmol, 1.00 equiv) in methanol (120 mL) was purged withnitrogen. Triethylamine (15.0 g, 149 mmol. 2.68 equiv) and palladium oncarbon (1.30 g) were added. After further purging the flask withnitrogen, the atmosphere was changed to hydrogen and the resultingsolution was stirred for 2 days at room temperature under atmosphericpressure. After purging the system with nitrogen, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:50-1:5) as eluentto furnish 3.50 g (38%) of the title compound as a yellow solid.

Compound 348.4. 5-Amino-6-methylnicotinic acid. Into a round-bottomflask, was placed a solution of methyl 5-amino-6-methylnicotinate (5.00g, 30.1 mmol, 1.00 equiv) and sodium hydroxide (20 g) in MeOH/H₂O(80/200 mL). The resulting solution was heated at reflux overnight.After cooling to ambient temperature, the methanol was removed underreduced pressure. The pH of the remaining aqueous phase was adjusted to4 with aqueous hydrogen chloride (2 M). The resulting mixture was thenconcentrated under reduced pressure to yield 5.00 g (crude) of the titlecompound as a yellow solid.

Compound 348.N-5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylpyridin-3-yl)-6-(pyrrolidin-1-yl)nicotinamide.The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compounds 348.4 and 1.5 inplace of 5-amino-2,4-dimethylbenzoic acid and compound 11.2respectively. m/z (ES+) 495 (M+H)⁺.

Compound 349.1. 2-Bromo-5-methylpyridine 1-oxide. Into a round-bottomflask, was placed a solution of 2-promo-5-methylpyridine (10.0 g, 58.1mmol, 1.00 equiv) in dichloromethane (250 mL). mCPBA (15.0 g, 86.9 mmol,1.50 equiv) was added in several hatches at room temperature. Theresulting solution was stirred overnight at 30° C., then diluted with 50mL of 2N sodium hydroxide (aq.). The OH value of the solution wasadjusted to 10 with 2N sodium hydroxide (aq.). The aqueous phase wasextracted with 3×100 mL of dichloromethane and the combined organiclayers were dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to yield 11.0 g (91%) of2-promo-5-methylpyridin-1-ium-1-olate as a yellow solid.

Compound 349.2. 2-Bromo-5-methyl-4-nitropyridine 1-oxide. Into around-bottom flask, was placed HNO₃ (15 mL), sulfuric acid (20 mL). Tothis was added compound 349.1 (11.0 g, 52.7 mmol, 1.00 equiv, 90%) inseveral batches at room temperature. The resulting mixture was stirredovernight at 100° C., then cooled to ambient temperature and quenchedwith 50 mL of ice water. The pH was slowly adjusted to 2-3 with sodiumhydroxide (aq. 2 M) and the resulting mixture was extracted with 3×50 mLof dichloromethane. The combined organic layers were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:2) as eluent to furnish 3.00 g (23%) of thetitle compound as a yellow solid.

Compound 349.3. Methyl 4-amino-5-methylpicolinate. Into a 250-mLautoclave (30 atm, CAUTION: Carry out behind a blast shield) purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 2-bromo-5-methyl-4-nitropyridine 1-oxide (compound 349.2, 3.00 g,12.9 mmol, 1.00 equiv) in methanol (120 mL). Triethylamine (2.60 g, 25.7mmol, 2.00 equiv) and Pd(dppf)Cl₂ (600 mg, 0.82 mmol, 0.06 equiv) wereadded to the reaction. The autoclave was purged and the mixture was thenstirred overnight under 30 atm of CO (g) at 90° C. After cooling toambient temperature, the mixture was concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with ethyl acetate: methanol (20:1) as eluent to furnish1.50 g (67%) of methyl 4-amino-5-methylpyridine-2-carboxylate as ayellow solid.

Compound 349.4. 4-Amino-5-methylpicolinic acid. A solution of methyl4-amino-5-methylpicolinate (compound 349.3, 1.50 g, 8.12 mmol, 1.00equiv, 90%) and 5N sodium hydroxide (aq., 15 mL) in methanol (15 mL) wasstirred overnight at room temperature, then concentrated under reducedpressure. The residue was diluted with 20 mL of H₂O and the pH wasadjusted to 3-4 with 2 M aqueous hydrogen chloride. The resultingprecipitate was collected by filtration and dried to yield 0.8 g (58%)of the title compound as a yellow solid.

Compound 349.N-(2-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-5-methylpyridin-4-yl)-6-(isopropylamino)nicotinamide.The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compounds 349.4 and 1.5 inplace of 5-amino-2,4-dimethylbenzoic acid and compound 11.2respectively. m/z (ES+) 483 (M+H)⁺.

Compound 350.1. 2-Bromo-3-methylpyridine 1-oxide. The title compound wasprepared (8.00 g, 85%) using a procedure similar to that used for thepreparation of compound 349.1 and using 2-bromo-3-methylpyridine (8.60g) in place of 2-bromo-5-methylpyridine.

Compound 350.2. 6-Bromo-5-methylpicolinonitrile. To a solution of2-bromo-3-methylpyridine 1-oxide (compound 350.1, 5.65 g. 30.1 mmol,1.00 equiv) in acetonitrile (50 mL) were added triethylamine (6.10 g,60.3 mmol, 2.00 equiv) and TMSCN (8.90 g, 3.00 equiv). The resultingsolution was heated to reflux and stirred overnight in an oil bath, thencooled to ambient temperature and concentrated under reduced pressure.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:5) as eluent to yield 2.00 g (34%) ofthe title compound as a yellow solid.

Compound 350.3. 6-Bromo-5-methylpicolinimidamide. Into a 50-mL sealedtube, was placed a solution of 6-bromo-5-methylpicolinonitrile (compound350.2, 900 mg, 4.57 mmol, 1.00 equiv) in methanol (40 mL). NH₃ (g) wasbubbled through the solution and the resulting solution was stirredovernight at 95° C. in an oil bath behind a blast shield. After coolingto ambient temperature, the mixture concentrated under reduced pressureto yield 800 mg (82%) of the title compound as a light brown solid.

Compound 350.4. 6-Amino-5-methylpicolinamide. Into a 50-mL sealed tube,was placed a solution of 6-bromo-5-methylpicolinimidamide (compound350.3, 800 mg, 3.74 mmol, 1.00 equiv) and CuSO₄ (80 mg) in NH₃.H₂O (40mL). The resulting mixture was stirred overnight at 80° C. behind ablast shield. After cooling to ambient temperature, the mixture was thenextracted with 2×50 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to yield 750 mg (crude) of the title compound as a brown solid.

Compound 350.5. 6-Amino-5-methylpicolinic acid hydrochloride. Intoaround-bottom flask was placed a solution of6-amino-5-methylpicolinamide (compound 350.4, 500 mg, 3.31 mmol, 1.00equiv) in hydrogen chloride (conc., 15 mL). The resulting solution washeated to reflux overnight in an oil bath, then concentrated underreduced pressure to yield 600 mg (crude) of the title compound as alight yellow solid.

Compound 350.N-(6-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-3-methylpyridin-2-yl)-6-(isopropylamino)nicotinamide.The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compounds 350.5 and 1.5 inplace of 5-amino-2,4-dimethylbenzoic acid and compound 11.2respectively. m/z (ES +) 483 (M+H)⁺.

Compound 351.1. Methyl 5-nitro-1H-pyrazole-3-carboxylate. Into around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of5-nitro-1H-pyrazole-3-carboxylic acid (5.00 g, 31.9 mmol, 1.00 equiv) inmethanol (150 mL). To this was added thionyl chloride (5.60 g, 47.8mmol, 1.50 equiv) dropwise at 0° C. The resulting solution was stirredfor 18 h at 30° C. in an oil bath, then concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:30-1:10) as eluentto furnish 5.00 g (78%) of the title compound as a brown solid.

Compound 351.2 and 351.3. Methyl1-methyl-5-nitro-1H-pyrazole-3-carboxylate and methyl1-methyl-3-nitro-1H-pyrazole-5-carboxylate. Into a round-bottom flask,which was purged and maintained with an inert atmosphere of nitrogen,was placed a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (3.00g, 17.5 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL). Potassiumcarbonate (4.84 g, 35.0 mmol, 2.00 equiv) and CH₃I (2.98 g, 21.0 mmol,1.20 equiv) were added at 0° C. The resulting solution was stirred for 2h at 40° C. in an oil bath. After cooling to ambient temperature, thesolids were removed by filtration followed by the addition of 120 mL ofice water. The mixture was extracted with 3×100 mL of ethyl acetate andthe combined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified byre-crystallization from ether. This resulted in 1.10 g (34%) of methyl1-methyl-3-nitro-1H-pyrazole-5-carboxylate as a white solid. m/z (ES+)186 (M+H)⁺. ¹H NMR, (300 MHz, DMSO-d₆, ppm): □ 7.57 (s, 1H), 4.22 (s,3H), 3.91 (s, 3H). The filtrate was concentrated under vacuum and thecrude product (2 g) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18,19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (10% CH₃CNup to 56.5% in 10 min); Detector, uv 254 nm. The fractions containingpure compound were combined and concentrated to yield 470 mg (15%) ofmethyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate as a white solid. m/z(ES+) 186 (M+H)⁺. ¹H-NMR, (300 MHz, DMSO-d₆, ppm): □□ 7.64 (1H, s), 4.24(3H, s), 3.87 (3H, s).

Compound 351.4. Methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate. To asolution of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate (351.2,0.48 g, 2.60 mmol) in MeOH (15 ml) under nitrogen was added palladium oncarbon (10%, 0.25 g). The flask was further degassed with nitrogen andfilled with H₂ through a balloon. The mixture was stirred at roomtemperature for 1.5 hours. After purging the system with nitrogen, thereaction mixture was filtered through a Celite cake and concentrated togive 363 mg (90%) of a white solid. m/z (ES+) 156 (M+H)⁺.

Compound 351.5. Methyl5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate. To a solutionof methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate (compound 351.4,0.088 g, 0.57 mmol) in THF (5 ml) was added triphosgene (0.084 g, 0.28mmol) followed by DIEA (0.2 ml, 1.14 mmol). After the mixture wasstirred at room temperature for 2 hours, isobutyl amine (0.225 ml, 2.28mmol) was added. The resulting mixture was stirred at room temperatureover night. The mixture was partitioned between water and EtOAc. TheEtOAc layer was washed with 1 M aqueous NaH₂PO₄ solution followed bybrine, dried with Na₂SO₄, and concentrated to give 120 mg (83%) of alight yellow solid. m/z (ES+) 255 (M+H)⁺.

Compound 351.6. 5-(3-Isobutylureido)-1-methyl-1H-pyrazole-3-carboxylicacid To a solution of methyl5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate (compound 351.5,0.12 g, 0.47 mmol) in MeOH (5 ml) was added 1 M LiOH in H₂O (1.42 ml,1.42 mmol). The mixture was stirred at room temperature for 5 hours. TLCshowed the reaction was complete. The mixture was acidified to pH 3-4 at0° C. and then was extracted with EcOAc (2×50 ml). The combined organiclayers were dried with Na₂SO₄, filtered, and concentrated to give 110 mg(100%) of a clear oil. m/z (ES+) 241 (M+H)⁺.

Compound 351.1-(3-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)-3-isobutylurea.A solution of 5-(3-Isobutylureido)-1-methyl-1H-pyrazole-3-carboxylicacid (compound 351.6, 0.11 g, 0.46 mmol), 4-(piperidin-4-yl)benzonitrileHCl salt (compound 1.5, 0.097 g, 0.4 6 mmol), EDCI (0.090 g, 0.51 mmol),HOBT (0.065 g, 0.51 mmol, with 20% H₂O) and DIEA (0.22 ml, 1.38 mmol) inDMF (5 ml) was stirred at room temperature overnight. The reactionmixture was then diluted with 50 ml of ethyl acetate and washed with2×20 ml of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified using prep.-TLC and developed using neat ethyl acetate to yield25 mg of the title compound as an off-white solid. m/z (ES +) 409(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H), 7.76 (d, 2H), 7.49 (d,2H), 6.48 (t, 1H), 6.37 (s, 1H), 4.84 (d, 1H), 4.63 (d, 1H), 3.65 (s,3H), 3.14 (m, 1H), 2.92. (t, 3H), 2.79 (m, 2H), 1.85 (m, 1H), 1.67 (m,1H), 1.57 (m, 2H), 0.87 (d, 6H).

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 346,347, 348, 349. 350, and 351:

Preparation similar to Cmpnd Compound compound #(s) # name CompoundStructure [m/z (ES+)] 352 1-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-isobutylurea

346 and 64 [447 (M + H)⁺] 353 N-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl) pyrrolidine-1-carboxamide

346 and 64 [445 (M + H)⁺] 354 1-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-(2-methoxyethyl) urea

346 and 64 [449 (M + H)⁺] 355 N-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 6-(isopropylamino) nicotinamide

346 [510 (M + H)⁺] 356 3-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 1-(2- methoxyethyl)-1-methylurea

346 and 64 [463 (M + H)⁺] 357 N-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 6-(4-methylpiperazin- 1-yl) nicotinamide

346 [551 (M + H)⁺] 358 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 6-(piperazin-1-yl)nicotinamide

346 [537 (M + H)⁺] 359 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 6-((2- methoxyethyl)(methyl)amino) nicotinamide

346 [540 (M + H)⁺] 360 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 6-((2- methoxyethyl) amino)nicotinamide

346 [526 (M + H)⁺] 361 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 6-((2- hydroxyethyl) amino)nicotinamide

346 [512 (M + H)⁺] 362 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 6-((2- hydroxyethyl)(methyl)amino) nicotinamide

346 [526 (M + H)⁺] 363 (S)-1-(5-(5- cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3- ((tetrahydrofuran- 2-yl)methyl)urea

346 and 64 [475 (M + H)⁺] 364 1-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin- 3-yl)-3-isobutylurea

346, 348, and 64 [448 (M + H)⁺] 365 1-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-(1-methylpiperidin- 4-yl)urea

346 and 64 [488 (M + H)⁺] 366 N-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin- 3-yl)-6-(pyrrolidin-1- yl)nicotinamide

346 and 348 [523 (M + H)⁺] 367 1-(5-(5-cyano- 3H-spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin- 3-yl)-3-(2-methoxyethyl) urea

346, 348, and 64 [450 (M + H)⁺] 368 1-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-((tetrahydrofuran- 3-yl) methyl)urea

346 and 64 [475 (M + H)⁺] 369 N-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin- 3-yl)-6-(isopropylamino) nicotinamide

346 and 348 [511 (M + H)⁺] 370 N-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin- 3-yl)-6-(dimethylamino) nicotinamide

346 and 348 [497 (M + H)⁺] 371 6-(azetidin-1- yl)-N-(5-(5- cyano-3H-spiro[isobenzo furan-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin-3- yl)nicotinamide

346 and 348 [509 (M + H)⁺] 372 N-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin- 3-yl)-6-((2-methoxyethyl) amino) nicotinamide

346 and 348 [527 (M + H)⁺] 373 N-(5-(7-(4- cyanophenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo [4,3-a]pyridin- 3-yl)-2- methylphenyl)pyrrolidine-1- carboxamide

347 and 64 [427 (M + H)⁺] 374 1-(5-(7-(4- cyanophenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo [4,3-a]pyridin- 3-yl)-2- methylphenyl)-3-(2- methoxyethyl) urea

347 and 64 [431 (M + H)⁺] 375 1-(5-(7-(4- cyanophenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo [4,3-a]pyridin- 3-yl)-2- methylphenyl)-3-isobutylurea

347 and 64 [429 (M + H)⁺] 376 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl)-3- isobutylurea

348 and 64 [420 (M + H)⁺] 377 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl)-3-(2- methoxyethyl) urea

348 and 64 [422 (M + H)⁺] 378 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl) pyrrolidine- 1-carboxamide

348 and 64 [418 (M + H)⁺] 379 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl)-6- (isopropylamino) nicotinamide

348 [483 (M + H)⁺] 380 1-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-(piperidin-4- yl)urea

348 and 64 [474 (M + H)⁺] 381 3-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 1-methyl-1-((tetrahydrofuran- 3-yl) methyl)urea

348 and 64 [489 (M + H)⁺] 382 1-(2-(4-(4- cyanophenyl) piperidine-1-carbonyl)-5- methylpyridin- 4-yl)-3- (tetrahydrofuran- 3-yl)urea

349 and 64 [434 (M + H)⁺] 383 1-(6-(4-(4- cyanophenyl) piperidine-1-carbonyl)-3- methylpyridin- 2-yl)-3- (tetrahydrofuran- 3-yl)urea

321 and 64 [434 (M + H)⁺] 384 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)- 6- (isobutylamino) nicotinamide

351 and 43 [486 (M + H)⁺] 385 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)- 6- (isopropylamino) nicotinamide

351 and 43 [472 (M + H)⁺] 386 N-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1H- pyrazol-5-yl)- 6- (isobutylamino) nicotinamide

351 and 43 [472 (M + H)⁺] 387 N-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1H- pyrazol-5-yl)- 6- (isopropylamino) nicotinamide

351 and 43 [458 (M + H)⁺] 388 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)- 3-isobutylurea

351 and 64 [409 (M + H)⁺] 389 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)- 3- isopropylurea

351 and 64 [395 (M + H)⁺] 390 1-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-5-yl)- 3- isopropylurea

351 and 64 [395 (M + H)⁺] 391 N-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-5-yl)- 6- (isobutylamino) nicotinamide

351 and 43 [486 (M + H)⁺]

Compound 392.1. 4-Cyclobutyl-5-formyl-2-methylbenzoic acid. Into a threeneck round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 230.1, 5.00 g, 12.7mmol, 1.00 equiv, 80%) in a solvent mixture of tetrahydrofuran and Et₂O(50/50 mL). This was followed by the addition of butyllithium (15 mL,2.50 equiv, 95%) dropwise with stirring at −78° C. To this was addedN,N-dimethylformamide (2.50 g, 32.5 mmol, 2.00 equiv). The resultingsolution was stirred for 1 h at −78° C. and then carefully quenched byslow addition of 50 mL of NH₄Cl (aq.). The pH was adjusted to 1-2 withhydrogen chloride (6 M). The resulting solution was diluted with 100 mLof ethyl acetate, then washed with 4×50 mL of brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:1) as eluent to furnish 1.62 g (41%) of4-cyclobutyl-5-formyl-2-methylbenzoic acid as a white solid.

Compound 392.2.4-(1-(4-Cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.Into a round-bottom flask, was placed a solution of4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 392.1, 490 mg, 1.57mmol, 1.00 equiv, 70%) in N,N-dimethylformamide (8 mL). Compound 1.5(500 mg, 1.57 mmol, 1.00 equiv), EDC.HCl (860 mg, 4.26 mmol, 2.00 equiv,95%) and 4-dimethylaminopyridine (550 mg, 4.28 mmol, 2.00 equiv, 95%)were added to the reaction mixture. The resulting solution was stirredovernight at room temperature, and then diluted with 30 mL of ethylacetate. The resulting mixture was washed with 4×30 mL of brine, thendried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:2) as eluent toyield 560 mg (74%) of the title compound as a white solid.

Compound 392.4-(1-(4-Cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, was placed a solution of4-[1-[(4-cyclobutyl-5-formyl-2-methylphenyl)carbonyl]piperidin-4-yl]benzonitrile(392.2, 300 mg, 0.74 mmol, 1.00 equiv, 95%) in N,N-dimethylformamide (10mL). 3-Bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 210 mg, 1.17mmol, 1.00 equiv), ammonia (82 mg, 0.59 mmol, 3.00 equiv, 25% aq.), andNH₄OAc (270 mg, 2.81 mmol, 4.50 equiv, 80%) were added and the resultingmixture was stirred overnight at 130° C. under nitrogen. After coolingto room temperature, the mixture was diluted with 50 mL of ethylacetate, washed with 4×50 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethyl acetate aseluent. The crude product (˜80 mg) was further purified by Prep-HPLCwith the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column,SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA andCH₃CN (26% CH₃CN up to 41% in 7 min, up to 100% in 3 min, down to 26% in2 min); Detector, Waters 2489 254 & 220 nm. The fractions containingpure compound were combined and lyophilized to yield 24.6 mg (7%) of thetitle compound as a white solid. m/z (ES+) 481 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.67 (d, J=7.8 Hz, 2H), 4.47 (d, J=8.1 Hz, 2H), 7.33 (br s,1H), 7.26 & 7.15 (2 singlets, amide rotamers, Ar—H, 1H), ˜4.9 (1Hpartially obscured by water peak), 4.68 (s, 2H), 4.06-3.88 (m, 3H),3.73-3.58 (m, 1H), 3.33-3.18 (m, 1H), 3.07-2.92 (m, 2H), 2.83-2.73 (m,2H), 2.44 & 2.34 (2 singlets, amide rotamers, 3H), 2.25-1.91 (m, 6H),1.91-1.50 (m, 4H). ¹H NMR (400 MHz, CDCl₃): δ 7.64 (m, 2H), 7.34 (m,2H), 7.13-6.93 (m, 2H), 4.99 (m, 1H), 4.75 (s, 2H), 3.98 (m, 2H), 3.73(m, 1H), 3.53 (m, 1H), 3.31-2.83 (m, 5H), 2.41 (m, 1H), 2.37-1.61 (m,1H), 1.44 (m, 1H).

Compound 393.4-(1-(2-Ethyl-4-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 but compound 211.2 was used in place of compound 2.2. m/z (ES+)455 (M+H)⁺.

Compound 394.4-(1-(4-Ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 393but compound 152.1 was used in place of methyl 2-bromo-4-methylbenzoate.m/z (ES+) 455 (M+H)⁺.

Compound 395.4-(1-(4-Ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 394but compound 11.2 HCl salt was used in place of compound 1.5. m/z (ES+)473 (M+H)⁺.

Compound 396.4-(1-(2,4-Diethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. The title compoundwas prepared using standard chemical manipulations and proceduressimilar to those used for the preparation of compounds 1 and 2 exceptcompounds 204.3 and 11.2 were used in place of compounds 2.2 and 1.5respectively. m/z (ES+) 487 (M+H)⁺.

Compound 397.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 except compound 204.3 was used in place of compound 2.2. m/z (ES+)510 (M+H)⁺.

Compound 398.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-ethyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1,2, and 394. m/z (ES+) 496 (M+H)⁺.

Compound 399.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1,2, and 394, but using compound 11.2 HCl salt in place of compound 1.5.m/z (ES+) 514 (M+H)⁺.

Compound 400.1. 3-Methyldihydro-2H-pyran-4(3H)-one. A 1-L three neckround-bottom flask was purged and maintained with a nitrogen atmosphereand a solution of LDA (2 M THF, 132 mL, 1.20 equiv) in tetrahydrofuran(300 mL). The mixture was cooled to −78° C., then a solution ofdihydro-2H-pyran-4(3H)-one (22.0 g, 22.0 mmol, 1.00 equiv) inhexamethylphosphoramide (40 mL, 230 mmol, 1.05 equiv) was addeddrop-wise followed by drop-wise addition of methyliodide (34 mL, 550mmol, 2.5 equiv) at −78° C. The resulting solution was stirred at −78°C. for 5 min, then at 25° C. for 5 min. The reaction was carefullyquenched with saturated aqueous NH₄Cl (80 mL) and extracted with ether(2×100 mL). The combined organics was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography with PE/Et₂O (5:1) as the eluent to obtain the titlecompound as a yellow oil (6.00 g, 24%).

Compound 400.2. 3-Bromo-5-methyldihydro-2H-pyran-4(3H)-one. A 250-mLthree neck round-bottom flask was purged and maintained with a nitrogenatmosphere. LDA (2.0 M in THF)(6 mL, 12 mmol, 1.20 equiv) andtetrahydrofuran (30 mL) were added. The solution was cooled to −78° C.and then TMSCl (7 mL, 55 mmol) was added drop-wise and stirred at −78°C. for 5 min. A solution of 3-methyldihydro-2H-pyran-4(3H)-one (compound400.1, 1.14 g, 9.99 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) wasadded drop-wise and the resulting mixture was stirred at −78° C. for 10min. The mixture was carefully quenched with a mixture of triethylamine(15 mL) and saturated aqueous NaHCO₃ (100 mL). The aqueous was extractedwith ether (2×50 mL), and the combined organics was washed with aqueouscitric acid (3×100 mL), dried (K₂CO₃), filtered and concentrated invacuo to obtain the intermediate enol silyl ether as a colorless oil.The enol silyl ether was dissolved in tetrahydrofuran (20 mL) and thesystem was purged with nitrogen. The mixture was cooled to 0° C., andthen N-bromosuccinimide (1.95 g, 11.0 mmol, 1.10 equiv) was addedportion-wise. The resulting mixture was stirred at 25° C. for 1 h, thenquenched with saturated aqueous NaHCO₃ (30 mL). The aqueous wasextracted with ether (2×30 mL), and the combined organics was dried(Na₂SO₄), filtered and concentrated in vacuo The residue was purified bysilica gel chromatography with PE/Et₂O (5:1) as the eluent to obtain thetitle compound as a colorless oil (1.00 g, 52%).

Compound 400.3.2-Ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoicacid. Into around-bottom flask, was placed a solution of3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2, 800 mg, 4.14mmol, 1.6 equiv) in N,N-dimethylformamide (5 mL). Ammonium hydroxide(25% NH₃ in H₂O) (530 mg, 7.8 mmol, 3.0 equiv), NH₄OAc (904 mg, 11.7mmol, 4.50 equiv) and 2-ethyl-5-formyl-4-methylbenzoic acid (compound211.4, 500 mg, 2.60 mmol, 1.00 equiv) were added to the flask. Theresulting mixture was stirred at 130° C. for 2 h, then concentrated invacuo. The residue was purified by silica gel chromatography withdichloromethane/methanol (70/1) as the eluent to obtain the titlecompound as a white solid (30.0 mg, 2%).

Compound 400.4-(1-(2-Ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, was placed a solution of2-ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoicacid (compound 400.3, 30 mg, 0.10 mmol, 1.0 equiv) in DMF/DCM (5/5 mL).4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 50 mg, 0.22mmol, 2.2 equiv), EDC (40 mg, 2.0 equiv) and 4-dimethylaminopyridine (28mg, 2.0 equiv) were added. The resulting solution was stirred overnightat 25° C., then quenched with water (10 mL). The mixture was extractedwith ethyl acetate (3×5 mL), and the combined organic layers was dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatraphy with ethyl acetate/petroleum ether (2:1) asthe eluent to obtain the title compound as a light yellow solid (3.2 mg,7%). m/z (ES+) 469 (M+H)⁺.

Compound 401.4-(1-(4-Cyclopropyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 392but compound 142.2 was used in place of compound 152.3. m/z (ES+) 467(M+H)⁺.

Compound 402.4-(1-(4-Cyclopropyl-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 392but compound 226.5 was used in place of compound 230.1. m/z (ES+) 481(M+H)⁺.

Compound 403. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 but compound 142.2 and dimethyl dicarbonate/DIEA were used inplace of compound 2.2 and acetic anhydride respectively. m/z (ES+) 524(M+H)⁺.

Compound 404.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclopropyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 but using compound 142.2 was used in place of compound 2.2. m/z(ES+) 508 (M+H)⁺.

Compound 405. 4-(1(4-Cyclobutyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile. Thetitle compound was prepared using standard chemical manipulations andprocedures similar to those used for the preparation of compound 392,except compound 11.2 HCl salt was used in place of compound 1.5. m/z(ES+) 499 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.97 (m, 2H), 7.97 (m, 2H),7.67-7.53 (m, 2H), 4.80 (s, 2H), 4.10 (m, 2H), 3.75 (m, 1H), 3.55 (m,2H), 3.27 (m, 1H), 2.90 (m, 2H), 2.53 and 2.43 (2 singlets, amiderotamers, ArCH₃, 3H), 2.38-1.80 (m, 10H).

Compound 406.1.5-(5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoicacid. To a solution of 4-cyclobutyl-5-formyl-2-methylbenzoic acid(compound 392.1, 2.00 g, 9.16 mmol, 1.00 equiv) in N,N-dimethylformamide(15 mL) were added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate(9.00 g, 16.2 mmol, 2.00 equiv), ammonium hydroxide (3.84 g, 27.4 mmol,3.00 equiv, 25%), and NH₄OAc (3.18 g, 41.3 mmol, 4.50 equiv). Theresulting mixture was stirred overnight at 130° C. under nitrogen. Aftercooling to ambient temperature, the mixture was diluted with 50 mL ofethyl acetate, washed with 3×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography withdichloromethane/methanol (20:1) as eluent to furnish 2.00 g (27%) of thetitle compound as a brown solid.

Compound 406.2. tert-Butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.To a solution of5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoicacid (compound 406.1, 1.00 g, 1.22 mmol, 1.00 equiv, 50%) inN,N-dimethylformamide (5 mL) were added 4-(piperidin-4-yl)benzonitrilehydrochloride salt (compound 1.5, 270 mg, 1.21 mmol, 1.00 equiv),EDC.HCl (460 mg, 2.40 mmol, 2.00 equiv), and 4-dimethylaminopyridine(296 mg, 2.42 mmol, 2.00 equiv). The resulting mixture was stirred at25° C. overnight. The mixture was then diluted with 30 mL of ethylacetate, washed with 3×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to yield 890 mg (63%)of the title compound as a brown solid.

Compound 406.3.4-(1-(4-Cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.A solution of tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(406.2, 600 mg, 0.620 mmol, 1.00 equiv, 60%) in dichloromethane (3 mL)and trifluoroacetic acid (1.5 mL) was stirred for 3 h at 25° C., thendiluted with 5 mL of hydrochloric acid (3 mol/L) and 10 mL of water. Theresulting mixture was washed with 3×20 mL of ethyl acetate and the pHwas then adjusted to 9 with sodium hydroxide (aq, 3 M). The resultingmixture was extracted with 4×20 mL of dichloromethane. The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure to yield 140 mg (37%) of the title compound as a brown solid.

Compound 406.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.To a solution of4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(406.3, 190 mg, 0.30 mmol, 1.00 equiv, 75%) in tetrahydrofuran (10 mL)were added NaBH(OAc)₃ (252 mg, 1.13 mmol, 3.00 equiv, 95%) and HCHO(37%) (2.2 mL, 2.00 equiv). The resulting mixture was stirred for 2 h at40° C. in an oil bath and then concentrated under reduced pressure. Theresidue was diluted with dichloromethane and washed with aqueoussaturated sodium bicarbonate and brine. The organic layer was dried(Na₂SO₄) and concentrated. The crude product (˜80 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with0.03% NH3H₂O and CH₃CN (36% CH₃CN up to 48% in 8 min, up to 100% in 1min, down to 36% in 1.5 min); Detector, Waters 2489 254 & 220 nm. Thefractions containing pure compound were combined and lyophilized toyield 23.4 mg (16%) of the title compound as a white solid. m/z (ES+)494 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d, J=6.0 Hz, 2H), 7.48 (d,J=6.0 Hz, 2H), 7.37-7.31 (m, 1H), 7.26 & 7.15 (2 singlets, amiderotamers, Ar—H, 1H), ˜4.9 (1H partially obscured by water peak),4.02-3.90 (m, 1H), 3.73-3.57 (m, 1H), 3.57 (s, 2H), 3.34-3.21 (m, 1H),3.06-2.94 (m, 2H), 2.90-2.77 (m, 4H), 2.54 (s, 3H), 2.45 & 2.34 (2singlets, amide rotamers, ArCH₃, 3H), 2.11-1.86 (m, 6H), 1.86-1.54 (m,4H).

Compound 407.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 11.2 HCl salt was used in place of compound 1.5.m/z (ES +) 512 (M+H)⁺.

Compound 408.4-(1-(4-)Methyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 406except 3-iodo-4-methylbenzoic acid was used in place of compound 230.1.m/z (ES+) 440 (M+H)⁺.

Compound 409.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.To a solution of4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(406.3, 180 mg, 0.300 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (5mL) were added dimethyl dicarbonate (176 mg, 1.31 mmol, 5.00 equiv) andDIEA (169 mg, 1.31 mmol, 5.00 equiv). The resulting solution was stirredovernight at 25° C. and then quenched with 20 mL of methanol. Theresulting mixture was concentrated under reduced pressure and the crudeproduct was purified by Prep-HPLC using the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (28% CH₃CN up to 43% in 8min, up to 100% in 3 min,down to 28% in 2 min); Detector, Waters 2489254 & 220 nm. The fractions containing pure compound were combined andlyophilized to yield 29.9 mg (19%) of the title compound as a whitesolid. m/z (ES+) 538 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.70 (m, 2H),7.50-7.35 (m, 4H), 4.90 (m, 1H), 4.70 (s, 2H), 4.00 (m, 2H), 3.80 (m,4H), 3.60 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.50 and2.40 (2 singlets, amide rotamers, ArCH₃, 3H), 2.16-2.00 (m, 6H),1.86-1.64 (m, 4H).

Compound 410. Methyl2-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 11.2 was used in place of compound 1.5. m/z (ES+)556 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.78 (m, 2H), 7.67 (m, 2H),7.35-7.20 (m, 2H), 4.80 (m, 1H), 4.55 (s, 2H), 4.00 (m, 1H), 4.84(m,2H), 3.77 (s, 3H), 3.60 (m, 1H), 3.28 (m, 1H), 2.80 (s, 2H), 2.47 and2.36 (2 singlets, amide rotamers, ArCH₃, 3H), 2.30-1.80 (m, 9H), 1.62(m, 1H), 1.32 (m, 1H).

Compound 411. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 226.5 was used in place of compound 230.1. m/z(ES+) 538 (M+H)⁺.

Compound 412.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 226.5 was used in place of compound 230.1. m/z(ES+) 494 (M+H)⁺.

Compound 413.1. 4-Cyclobutyl-3-iodobenzoic acid. A solution of compound168.2 (11.0 g, 34.8 mmol, 1.00 equiv) and sodium hydroxide (4.00 g, 100mmol, 3.00 equiv) in methanol (˜100 mL) was stirred at 50° C. overnight.After cooling to ambient temperature, the mixture was concentrated todryness. The residue was taken up in water (50 mL) equiv and washed withethyl acetate. The pH of the aqueous layer was adjusted to 3-4 with 6 Maqueous hydrogen chloride. The resulting precipitate was collected byfiltration and dried to yield 8.60 g (82%) of the title compound as awhite solid.

Compound 413.4-(1-4-Cyclobutyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound392, except compound 413.1 was used as in place of compound 230.1. m/z(ES+) 477 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.76-7.65 (m, 5H), 7.48 (m,2H), 5.00 (m, 1H), 4.80 (s, 2H), 4.10 (m, 2H), 3.80 (m, 2H), 3.45 (m,1H), 3.04 (m, 2H), 2.90 (m, 2H), 2.18-1.95 (m, 6H), 1.85-1.77 (m, 4H).

Compound 414.4-(1-(4-Cyclobuty)-3-(3,4,6,7-tetrahydropyrano[3,4]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound413, except compound 11.2 HCl salt was used in place of compound 1.5.m/z (ES+) 485 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.82-7.77 (m, 3H),7.68-7.65 (m, 4H), 4.80 (m, 3H), 4. 90 (m, 2H), 3.83-3.46 (m, 3H), 2.90(m, 2H), 2.29 (m, 1H), 2.18-1.83 (m, 10H).

Compound 415.4-(1-(4-Cyclobutyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound414, except 3-methyldihydro-2H-pyran-4(3H)-one was used in place ofdihydro-2H-pyran-4(3H)-one. m/z (ES+) 499 (M+H)⁺.

Compound 416.4-(1-4-Cyclopropyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound413, except bromo(cyclopropyl)magnesium and3-methyldihydro-2H-pyran-4(3H)-one were used in place ofbromo(cyclobutyl)magnesium and dihydro-2H-pyran-4(3H)-one respectively.m/z (ES+) 467 (M+H)⁺.

Compound 417.4-(1-(4-Cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 413.1 was used in place of compound 230.1. m/z(ES+) 480 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.72-7.63 (m, 4H), 7.56 (s,1H), 7.49 (m, 2H), 4.82 (m, 1H), 4.56 (s, 2H), 3.89 (m, 2H), 3.80 (m,2H), 3.08 (m, 2H), 3.04 (s, 3H), 2.99 (m, 2H), 2.18-1.66 (m, 11H).

Compound 418.4-(1-(4-Cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound417, except compound 11.2 HCl salt was used in place of compound 1.5.m/z (ES+) 498 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.79 (m, 2H), 7.74-7.59(m, 5H), 4.73 (br s, 1H), 4.54 (br s, 2H), 3.94 (m, 2H), 3.76 (br s,2H), 3.61 (br s, 1H), 3.20 (br s, 2H), 3.16 (s, 3H), 2.39-1.96 (m, 10H),1.79 (m, 1H).

Compound 419. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 413.1 was used in place of compound 230.1. m/z(ES+) 524 (M+H).

Compound 420. Methyl2-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compounds 413.1 and 11.2 were used in place of compounds230.1 and 1.5 respectively. m/z (ES+) 542 (M+H).

Compound 421. Ethyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 413.1 and diethyl dicarbonate were used in place ofcompound 230.1 and dimethyl dicarbonate respectively. m/z (ES+) 538(M+H).

Compound 422. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound421, except bromo(cyclopropyl)magnesium and dimethyl diethyl dicarbonatewere used in place of bromo(cyclobutyl)magnesium and diethyl dicarbonaterespectively. m/z (ES+) 510 (M+H).

Compound 423.4-(1-(2,4-Dimethyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.A mixture of4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 2.9, 62 mg), oxetan-3-one (18 □l), sodium cyanotrihydroborate(18 mg), and acetic acid (80 □l) in MeOH/THF (1:1 v/v) was stirred for16 hours. The reaction was then diluted with dichloromethane, washedwith saturated sodium bicarbonate solution followed by brine. Theorganic layer was dried (MgSO₄) and concentrated. The residue waspurified by preparative TLC at 8% MeOH in DCM to give 42 mg white solid(60%). m/z (ES+) 496 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.63 (d,2H), 7.32 (d, 2H), 7.27 and 7.20 (2 singlet, amide rotamers, 1H), 7.02(s, 1H), 4.96 (s, 1H), 4.74 (m, 4H), 3.88-3.77 (m, 1H), 3.63 (d, 1H),3.49 (d, 2H), 3.08 (t, 1H), 2.97-2.62 (m, 6H), 2.45 (d, 3H), 2.31 and2.22 (2 singlets, amide rotamers, 3H), 2.11-1.40 (m, 4H).

Compound 424.4-(1-(5-(5-Cyclopropyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 423.m/z (ES+) 480 (M+H)⁺. □¹H NMR (400 MHz, Chloroform-d) δ 10.58, 7.61 (d,2H), 7.33 (d, 2H), 7.23 and 7.15 (2 singlet, amide rotamers, 1H), 6.97(s, 1H), 4.93 (s, 1H) 3.80-3.66 (m, 2H), 3.64-3.49 (m, 1H), 3.02 (m,3H), 2.91-2.64 (m, 4H), 2.41 (d, 3H). 2.28 and 2.18 (2 singles, amiderotamers, 3H), 2.07-1.86 (m, 2H), 1.84-1.37 (m, 2H), 0.66-0.40 (m, 4H).

Compound 425. 4-(1-(2,4-Dimethyl-5-(5-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 406 butusing compound 2.9 in place of compound 406.3. m/z (ES+) 454 (M+H)⁺.

Compound 426.4-(1-(5-(5-Ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 423.m/z (ES+) 468 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.63 (d, 2H),7.40-7.19 (m, 3H), 7.04 (s, 1H), 4.95 (s, 1H), 3.75-3.51 (m, 3H), 3.09(m, 1H), 2.95-2.77 (m, 6H). 2.71 (m, 2H), 2.46 (s, 3H), 2.30 and 2.21 (2singlets, amide rotamers, 3H), 2.12-1.89 (m, 1H), 1.85-1.43 (m, 3H),1.22 (m, 3H).

Compound 427.4-(1-(5-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.A mixture of4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 2.9, 88 mg). 1-bromo-2-fluoroethane (150 □l), potassium iodide(50 mg), and triethyl amine (140 □l) in DMF (2 ml) was stirred for 48hours. The reaction mixture was then diluted with dichloromethane andwashed with brine. The organic layer was dried (MgSO₄) and concentrated.The residue was purified by prep. TLC using 8% MeOH in DCM to give 51 mgof a white solid (52%). m/z (ES+) 486 (M+H)⁺. ¹H NMR (400 MHz,Chloroform-d) 7.63 (d, 2H), 7.32 (d, 2H), 7.28 and 7.20 (2 singlets,amide rotamers, 1H), 7.00 (s, 1H), 4.93 (m, 1H), 4.67 (dt, J₁=47.6 Hz,J₂=4.9 Hz, 2H), 3.71 (d, 2H), 3.62 (d, 1H), 3.03-2.71 (m, 8H), 2.43 (d,3H), 2.29 and 2.19 (2 singlets, amide rotamers, 3H), 2.08-1.89 (m, 2H),1.85-1.49 (m, 2H), 3.18-3,05 (m, 1H).

Compound 428.4-(4-Fluoro-1-(5-(5-(2-fluoroethyl)-4,5,6,7-tetrahydro4H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 427 butusing compound 11.2 HCl salt instead of compound 1.5. m/z (ES+) 504(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, 2H), 7.50 (d, 2H),7.28 and 7.21 (2 singlet, amide rotamers, 1H), 7.00 (s, 1H), 4.92-4.77(m, 1H), 4.66 (dt, J₁=47.7 Hz, J₂=4.8 Hz, 2H), 3.68 (d, 2H), 3.58-3.35(m, 2H), 3.33-3.11 (m, 1H), 2.95 (dt, 4H), 2.76 (d, 2H), 2.42 (s, 3H),2.28 and 2.20 (2 singlets, amide rotamers, 3H), 2.16-1.72 (m, 4H).

Compound 429.1. 1-tert-Butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate. Toa solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100mmol, 1.00 equiv) in ether (60 mL) −30° C. was added dropwise a solutionof BF₃.Et₂O (16.0 mL, 1.30 equiv) in ether (20 mL). After stirring 30min at −30° C., a solution of ethyl 2-diazoacetate (16.0 g, 140 mmol,1.30 equiv) in ether (20 mL) was added dropwise to the reaction at −30°C. The resulting solution was stirred for 1 h at −30° C., then warmed to25° C. and stirred for 2 h. The reaction was then quenched with 100 mLof 30% aqueous potassium carbonate. The resulting mixture was extractedwith 2×250 mL of ethyl acetate, and the combined organic layers werewashed with 2×50 mL of brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1/10) as eluentto furnish 19.0 g (66%) of the title compound as a light yellow oil.

Compound 429.2. tert-Butyl 4-oxoazepane-1-carboxylate. To a solution1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (429.1, 19.0 g, 66.6mmol, 1.00 equiv) in 1,4-dioxane (190 mL) was added dropwise sodiumhydroxide (4.00 g, 100 mmol, 1.50 equiv) in water (100 mL). Theresulting mixture was stirred at room temperature overnight. The pH wasthen adjusted to 4-5 with hydrogen chloride (aq. 3 M) and the resultingsolution was extracted with 2×50 mL of ethyl acetate. The combinedorganic layers were washed with 2×10 mL of brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The cruderesidue was purified by silica gel chromatography using ethylacetate/petroleum ether (1:3) as eluent to furnish 11.0 g (77%) of thetitle compound as a yellow oil.

Compound 429.3. tert-Butyl 4-bromo-5-oxoazepane-1-carboxylate. To asolution tert-butyl 4-oxoazepane-1-carboxylate (429.2, 11.0 g, 51.6mmol, 1.00 equiv) in chloroform (220 mL) 0° C. was added dropwisesolution of Br₂ (12.4 g, 77.6 mmol, 1.50 equiv) in chloroform (110 mL).The resulting mixture was stirred at room temperature overnight. Theformed solids were collected by filtration and taken up in 200 mL ofdichloromethane. Et₃N (12.2 g) and (Boc)₂O (8.70 g. 40.3 mmol, 1.00equiv) were added to the mixture at 0° C. The resulting solution wasstirred for 3 h at room temperature, and then concentrated underpressure. The crude residue was purified by silica gel chromatographyusing ethyl acetate/petroleum ether (1:10) as eluent to give 4.00 g(27%) of the title compound as a yellow oil.

Compound 429.4. tert-Butyl-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate.To a solution of tert-butyl 4-bromo-5-oxoazepane-1-carboxylate (429.3,844 mg, 2.89 mmol, 2.00 equiv) in N,N-dimethylformamide (5 mL) wereadded compound 16.4 (500 mg, 1.44 mmol, 1.00 equiv), NH₄OH (606 mg, 4.33mmol, 3.00 equiv, 25%), and NH₄OAc (500 mg, 6.49 mmol. 4.50 equiv). Theresulting mixture was stirred overnight at 130° C. under nitrogen. Aftercooling to ambient temperature, 30 mL of ethyl acetate was added. Theresulting mixture was washed with 3×20 mL of brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate as eluent toyield 343 mg (43%) of the title compound as a brown solid.

Compound 429.5.4-(1-(5-(1,4,5,6,7,8-Hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitriletrifluoroacetate. To a solution of compound 429.4 (550 mg, 0.990 mmol,1.00 equiv) in DCM (3 mL) was added trifluoroacetic acid (1.3 mL). Afterstirring at 25° C. for 4 h, the mixture was concentrated under reducedpressure and dried to yield 400 mg (71%) of the title compound as abrown solid.

Compound 429.4-(1-(5-(6-Acetyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except compound 429.5 was used in place of compound 2.9. m/z (ES+) 496(M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.65 (d, J=8.1 Hz, 2H), 7.44-7.32 (m,4H), 4.90 (m, 1H), 3.86 (m, 2H), 3.60 (m, 1H), 3.20 (m, 2H), 3.00 (m,6H), 2.40-2,31 (m, 6H), 2.20 (s, 3H), 2.00-1.60 (m, 5H).

Compound 430. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 429.5 was used in place of compound 406.3. m/z(ES+) 496 (M+H)⁺.

Compound 431.4-(1-(5-(6-Isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.To a solution of4-(1-(5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitriletrifluoroacetate (429.5, 80.0 mg, 0.140 mmol, 1.00 equiv) inN,N-dimethylformamide (5 mL) were added 2-iodopropane (270 mg, 1.59mmol, 9.00 equiv) and DIEA (205 mg, 1.59 mmol, 9.00 equiv). Theresulting solution was stirred overnight at 80° C. in an oil bath. Aftercooling to ambient temperature, the mixture was diluted with 50 mL ofethyl acetate, washed with 3×20 mL of brine, dried (Na₂SO₄), andconcentrated. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:10) as eluent. Theproduct (50 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, Xbridge Prep C18, 5 um,19*150 mm; mobile phase, water with 0.03% NH₃H₂O and CH₃CN (38.0% CH₃CNup to 51.0% in 8 min, up to 100.0% in 2 min, down to 38.0% in 1 min);Detector, Waters 2489 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 15.0 mg (21%) of thetitle compound as a white solid. m/z (ES+) 496 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 7.69 (d, J=8.0 Hz, 2H), 7.49 (m, 2.H), 7.33-7.23 (m, 2H), 4.86(m, 1H), 3.65 (m, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.99 (m, 6H), 2.80(m, 4H), 2.45 (s, 3H), 2.40 and 2.29 (2 singlets, amide rotamers, 3H),2.10 (m, 1H), 1.70 (m, 3H), 1.15 (d, J=6.8 Hz, 6H).

Compound 432.4-(1-(5-(5-Ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 431except compound 2.9 was used in place of compound 429.5. m/z (ES+) 482(M+H)⁺.

Compound 433.4-(1-(4-Cyclopropyl-5-(5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound431, except compound 142.2 and tert-butyl3-bromo-4-oxopiperidine-1-carboxylate were used in place of compound152.3 and tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (429.2)respectively. m/z (ES+) 508 (M+H)⁺.

Compounds 434 and 435.4-(1-(2,4-Dimethyl-5-(4,5,7,8-tetrahydro-1H-oxepino[4,5-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrileand4-(1-(2,4-dimethyl-5-(4,6,7,8-tetrahydro-1H-oxepino[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compounds were prepared as a separable mixture using standardchemical manipulations and procedures similar to those used for thepreparation of compound 429, except oxepan-4-one was used in place ofcompound tert-butyl 4-oxoazepane-1-carboxylate (429.2). 434: m/z (ES+)455 (M+H)⁺: 435: m/z (ES+) 455 (M+H)⁺.

Compound 436.4-(1-(5-(6-(2-Fluoroethyl)-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound427, except compound 429.5 was used in place of compound 2.9. m/z (ES+)500 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=8.1 Hz, 2H), 7.43 (m,2H), 7.28-7.20 (m, 2H), 4.86 (m, 1H), 4.60 (dt, J₁=47.7 Hz, J₂=4.8 Hz,2H), 3.60 (m, 1H), 3.20 (m, 1H), 3.00 (m, 8H), 2.80 (m, 4H), 2.40 (s,3H), 2.35 and 2.24 (2 singlets, amide rotamers, 3H), 1.99 (m, 1H), 1.70(m, 3H).

Compound 437.4-(1-(4-Cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound418, except compound 429.3 was used in place of compound tert-butyl3-promo-4-oxopiperidine-1-carboxylate. m/z (ES+) 512 (M+H)⁺.

Compound 438.4-(1-(4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound407, except compound 429.3 was used in place of compound tert-butyl3-promo-4-oxopiperidine-1-carboxylate. m/z (ES+) 526 (M+H)⁺.

Compound 439.4-(1-(4-Cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound417, except compound 429.3 was used in place of compound tert-butyl3-promo-4-oxopiperidine-1-carboxylate. m/z (ES+) 494 (M+H)⁺.

Compound 440.4-(1-(4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 429.3 was used in place of compound tert-butyl3-promo-4-oxopiperidine-1-carboxylate. m/z (ES+) 508 (M+H)⁻.

Compound 441.(R)-1-(2-Chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethylphenyl)-3-((tetrabydrofuran-2-yl)methyl)urea.The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compound 67 andusing compound 178.2 in place of compound 48.1. m/z (ES+) 513 (M+H)⁺.

Compound 442.(R)-1-(2-Chloro-4-ethyl-5-(4-fluoro-4-(4-fluorophenyl)piperidine-1-carbonyl)phenyl)-3-((tetrahydrofuran-2-yl)methyl)urea.The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compound 67 andusing compound 178.2 in place of compound 48.1. m/z (ES+) 506 (M+H)⁺.

Compound 443.1. Methyl 4-cyclobutyl-3-nitrobenzoate. To a solution ofmethyl 4-cyclobutylbenzoate (compound 168.1, 3.80 g, 20.0 mmol, 1.00equiv) in acetic anhydride (12 mL) 0° C. was added dropwise fuming HNO₃(5 mL, 97%). The resulting mixture was stirred at 30° C. in an oil bath.After 2 h, 30 mL of water was carefully added and the mixture wasextracted with 2×30 mL of ethyl acetate. The combined organic layerswere washed with aqueous saturated NaHCO₃ (note: gas evolution), driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:25) as eluent to furnish 3.00 g (64%)of the title compound as a light yellow oil.

Compound 443.2. Methyl 3-amino-4-cyclobutylbenzoate. A flask containinga solution of methyl 4-cyclobutyl-3-nitrobenzoate (compound 443.1, 2.50g, 10.6 mmol, 1.00 equiv) in methanol (30 mL) was purged with nitrogen.Palladium on carbon (10%, 60% water, 1.2 g) was added and the flask wascarefully purged further with nitrogen. The atmosphere was then changedto hydrogen and the mixture was stirred overnight at 20° C. Afterpurging the system with nitrogen, the solids were then removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:5) as eluent to yield 1.60 g (73%) of thetitle compound as a white solid.

Compound 443.3. 3-Amino-4-cyclobutylbenzoic acid. Into around-bottomflask, was placed a solution of methyl 3-amino-4-cyclobutylbenzoate(1.00 g, 4.87 mmol, 1.00 equiv) and sodium hydroxide (compound 443.2,800 mg, 20.0 mmol, 4.00 equiv) in a solvent mixture of methanol and H₂O(20/10 mL). The resulting solution was stirred for 8 h at 20° C. Aftercooling to ambient temperature, the organic solvent was removed underreduced pressure. The pH of the remaining aqueous layer was adjusted to4-5 with HCl (aqueous, 1 M). The resulting precipitate was thencollected by filtration and dried to furnish 500 mg (54%) of the titlecompound as a white solid.

Compound 443.4.4-(1-(3-Amino-4-cyclobutylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using a procedure similar to that usedfor the preparation of compound 42.2, but using compound 443.3 in placeof compound 42.1.

Compound 443.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 64,using compound 443.4 and (R)-tetrahydrofuran-3-amine in place ofcompound 42.2 and (R)-(tetrahydrofuran-2-yl)methanamine respectively.m/z (ES+) 491 (M+H)⁺.

Compound 444.(S)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylphenyl)-3-(tetrahydrofuran-3-yl)urea.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound443, using (S)-tetrahydrofuran-3-amine in place of(R)-tetrahydrofuran-3-amine. m/z (ES+) 491 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.83-7.77 (m, 3H), 7.69 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.1 Hz,1H), 7.22 (dd, J=7.8 Hz, J=1.5 Hz, 1H), 4.80-4.62 (m, 1H), 4.39-4.31 (m,1H), 4.02-3.78 (m, 4H), 3.72-3.49 (m, 3H), ˜3.3 (1H partially obscuredby methanol solvent peak), 2.50-2.37 (m, 2H), 2.37-1.78 (m, 10H).

Compound 445.1. Methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate.To a solution of methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate (compound238.1, 500 mg, 2.03 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) at 0°C. was added dropwise a solution of LiHMDS (680 mg, 4.06 mmol, 2.00equiv) in tetrahydrofuran (5 mL). After 30 min of stirring at 0° C., asolution of propanoyl chloride (280 mg, 3.03 mmol, 1.50 equiv) intetrahydrofuran (5 mL) was added dropwise. The resulting mixture wasstirred for 3 h at 15° C., and then concentrated under reduced pressure.The residue was diluted with 40 mL of ethyl acetate, washed with ofbrine (3×40 mL), dried (Na₂SO₄), and concentrated under reducedpressure. This resulted in 500 mg (crude) of the title compound as abrown oil.

Compound 445.2. Methyl4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoate. To a solutionof methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate (compound445.1, 300 mg, 0.990 mmol, 1.00 equiv) in methanol (15 mL) was addedNH₂NH₂.H₂O. The resulting solution was stirred for 1.5 h at 80° C. in anoil bath, and then concentrated under reduced pressure. The residue wasdiluted with 100 mL of ethyl acetate, then washed with 3×100 mL ofbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:5) as eluent toyield 188 mg (64%) of the title compound as a yellow oil.

Compound 445.3. 4-Cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoicacid. To a solution of methyl4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoate (compound445.2, 188 mg, 0.630 mmol, 1.00 equiv) in methanol (6 mL) was addedaqueous sodium hydroxide (76.0 mg, 1.90 mmol, 3.00 equiv in 3 mL water).The resulting solution was stirred for 2 h at 70° C. in an oil bath.After cooling to ambient temperature, the mixture was concentrated underreduced pressure. The residue was diluted with 20 mL of H₂O. The pH ofthe mixture was adjusted to ˜4 with aqueous HCl (2 M). The mixture wasthen extracted with 3×20 mL of ethyl acetate. The combined organiclayers were washed with 3×20 mL of brine, dried (Na₂SO₄), andconcentrated under reduced pressure. This resulted in 0.180 g (crude) ofthe title compound as a yellow oil.

Compound 445.4-(1-(4-Cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile.To a solution of4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic acid (compound445.3, 130 mg, 0.460 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL)were added 4-(Piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg,0.460 mmol, 1.00 equiv), EDCI (176 mg, 0.920 mmol, 2.00 equiv), and4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equiv). The resultingsolution was stirred for 2 h at 30° C., and then diluted with 40 mL ofethyl acetate. The mixture was washed with 3×40 mL of brine, dried(Na₂SO₄), and concentrated under reduced pressure. The crude product waspurified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase,water with 0.05% TFA and CH₃CN (59.0% CH₃CN up to 73.0% in 6 min, up to100.0% in 7 min, down to 59.0% in 1 min); Detector, Waters 2489 254 &220 nm. The fractions containing pure compound were combined andlyophilized to yield 150 mg (72%) of the title compound as a whitesolid. m/z (ES+) 453 (M+H)⁺.

Compound 446.1 Methyl4-cyclobutyl-2-methyl-5-((trimethylsilyl)ethynyl)benzoate. A mixture ofmethyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 1.32 g, 4mmol), trimethylsilylacetylene (663 □l, 4.8 mmol), Pd(PPh₃)₂Cl₂ (85 mg,0.12 mmol) and copper iodide (CuI, 46 mg, 0.24 mmol) in THF (8 ml) andtriethylamine (2 ml) was degassed and then heated to 80° C. for 1.5hours under nitrogen. After cooling to ambient temperature, the reactionwas filtered through celite and concentrated. The residue was dissolvedin ethyl acetate (EtOAc), washed with brine, dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography (SiO₂; 3%EtOAc in Hexane) to give 1.17 g (97%) of the title compound as a liquid.¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.15 (s, 1H), 4.01-3.75 (m, 4H),2.63 (s, 3H), 2.54-2.31 (m, 2H), 2.27-2.12 (m, 2H), 2.12-1.98 (m, 1H),1.94-1.80 (m, 1H), 0.28 (s, 9H).

Compound 446.2. Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate. To asolution of compound 446.1 (1.17 g, 3.9 mmol) in THF (6 ml) at −20° C.was added 4.1 ml TBAF (1.0 M in THF). The mixture was stirred for 30minutes at this temperature and was then diluted with water (15 ml) andextracted with EtOAc twice. The combined organic phases were washed withbrine, dried (MgSO₄), and concentrated. The residue was purified byflash chromatography (SiO₂; 2% EtOAc in Hexane) to give 816 mg (91%) ofthe title compound as a liquid. m/z (ES−) 227 (M−H)⁻. ¹H NMR (400 MHz,CDCl₃) δ 8.05 (s, 1H), 7.20 (s, 1H), 4.02-3.80 (m, 4H), 3.25 (s, 1H),2.64 (s, 3H), 2.52-2.38 (m, 2H), 2.29-2.13 (m, 2H), 2.12-1.98 (m, 1H),1.93-1.79 (m, 1H).

Compound 446.3. Methyl 4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate. Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate (compound446.2, 180 mg, 0.69 mmol) was dissolved in TMSN₃ (1 ml) in sealed tube.The reaction was heated to 170° C. for 24 hours behind a blast shieldthen cooled down to 0° C. EtOAc (10 ml) and water (20 ml) were added.The resulting mixture was stirred at RT for 1 hr. The organic phase wasthen washed with brine, dried (MgSO₄), and concentrated. The residue waspurified by flash chromatography (SiO₂; 0-30% EtOAc in Hexane) to give92 mg (49%) of the title compound as a liquid. m/z (ES+) (272) (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.83 (s, 1), 7.35 (s, 1H), 3.90(s, 4H), 2.69 (s, 3H), 2.27-2.15 (m, 2H), 2.13-2.03 (m, 2H), 1.99-1.90(m, 1H), 1.86-1.76 (m, 1H).

Compound 446.4. 4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl) benzoicacid. A solution of methyl4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate (compound 446.3,92 mg, 0.34 M) in 2N NaOH (1.5 ml) and methanol (MeOH) (4 ml) was heatedat 50° C. for 16 hours. After cooling to room temperature, the methanolwas removed under reduced pressure. The residue was neutralized with 2NHCl to pH 3-4 and extracted with EtOAc. The organic phase was thenwashed with brine, dried (MgSO₄), and concentrated to yield 83 mg of awhite solid that was used without further purification. m/z (ES−) 256(M−H)⁻.

Compound 446. 4-(1-(4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoyl) piperidin-4-yl) benzonitrile. A mixture of the above acid(compound 446.4, 44 mg, 0.17 mmol), compound 1.5 (42 mg, 0.19 M), EDCI(49 mg, 0.26 mmol), HOBt (33 mg, 0.19 mmol) and DIEA (120 □l, 0.68 mmol)in DMF (1 ml) was stirred at room temperature for 2.5 hours. Thereaction was then diluted with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, and concentrated.The residue was purified by flash chromatography (SiO₂; 8% Methanol indichloromethane) and to yield 46 mg foam of the title compound (70%).m/z (ES+) 426 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.20 (s, 1H), 7.70 (d,1H), 7.66-7.49 (m, 2H), 7.44-7.21 (m, 4H), 5.01 (d, 1H), 3.83 (p, 1H),3.72 (d, 1H), 3.27-3.06 (m, 1H), 2.91 (m, 2H), 2.46 (2 singlets, amiderotamers, 3H), 2.27-1.89 (m, 3H), 1.86-1.43 (m, 7H).

Compound 447. 4-(1-(4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoyl)-4-fluoropiperidin-4-yl) benzonitrile. The title compound wasprepared using procedures similar to those used for preparation ofcompound 446 and using compound 11.2 HCl salt in place of compound 1.5.m/z (ES+) (444) (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.00(s, 1H), 7.77 (s,1H), 7.67 (m, 2H), 7.49 (d, 2H), 7.37 (m, 2H), 4.92 (d, 1H), 3.85 (t,1H), 3.61 (m, 1H), 3.52 (m, 1H), 3.25 (m, 1H), 2.45 (2 singlets, amiderotamers, 3H), 2.28-1.89 (m, 8H), 1.85 (m, 2H).

Compound 448.1. Methyl5-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoate. To asolution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound 130.1,500 mg, 2.24 mmol. 1.00 equiv) in ethanol (5 mL) was added sodiumbicarbonate (396 mg, 4.71 mmol, 1.00 equiv) and3-bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 186 mg, 1.04 mmol,1.00 equiv). The resulting solution was stirred overnight at 80° C.under nitrogen. After cooling to room temperature the mixture wasconcentrated under reduced pressure. The residue was taken up 10 mL ofwater and ethyl acetate. The aqueous phase was extracted with 2×20 mL ofethyl acetate and the combined organic layers were dried (MgSO₄), andconcentrated under reduced pressure to yield 400 mg (56%) of the titlecompound as a yellow solid.

Compound 448.2.5-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoic acid. Asolution of compound 448.1 (304 mg, 1.00 mmol) and sodium hydroxide(aqueous, 280 mg, 7.00 mmol in 3 mL water) in methanol (5 mL) wasstirred for 1 h at 56° C. in an oil bath. After cooling to ambienttemperature, the methanol was removed under reduced pressure. The pH ofthe remaining aqueous layer was adjusted to 3-4 with hydrogen chloride(aq., 2 M). The resulting precipitate was collected by filtration anddried in an oven under reduced pressure to yield 230 mg (79%) of thetitle compound as a yellow solid.

Compound 448.4-(1-(5-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.A solution of compound 448.2 (100 mg, 0.35 mmol, 1.00 equiv) inN,N-dimethylformamide (3 mL), DIEA (140 mg, 1.08 mmol, 3.00 equiv), andHBTU (197 mg, 0.52 mmol, 1.50 equiv) was stirred for 0.5 h at 25° C. Asolution of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,92.2 mg, 0.41 mmol, 1.10 equiv) in DIEA (1 mL) was added dropwise. Theresulting solution was stirred for 0.5 h at 25° C., then quenched with10 mL of water. The aqueous phase was extracted with 2×20 mL of ethylacetate and the combined organic layers were washed with 1×20 mL ofwater, 1×20 mL of brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:1) as eluent. The product was further purified by Prep-HPLC using thefollowing conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (25%CH₃CN up to 80% in 7 min, up to 100% in 1 min, down to 25% in 1 min);Detector, Waters 2489 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 134.9 mg (85%) of thetitle compound as a white solid. m/z (ES+) 458 (M+H)⁺.

Compound 449.1 and Compound 400.1.3,3-Dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) and3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1). To a solution ofLDA (2.0 M in heptanes/THF/ethylbenzene) (28 mL, 55 mmol) was addeddihydro-2H-pyran-4(3H)-one (4.612 g, 46 mmol) in THF (50 mL) drop-wiseunder argon at −78° C. The mixture was stirred at −78° C. for 5 minutes,then iodomethane (14 mL, 225 mmol) in THF (500 ml) was added. Theresulting mixture was allowed to warm to 0° C. and stirred for 2 hoursat 0° C. The reaction was allowed to warm to room temperature for 5 min,then cooled back to 0° C. and quenched with saturated ammonium chloride(30 mL) and the mixture was extracted with ether (2×50 mL). The combinedorganics was washed with brine (50 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (15% ethyl acetate in hexanes) to yield3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) as an oil (694mg, 13%) and 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1) as anoil (860 mg, 16%).

Compound 449.2. 5-Bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one. Asolution of lithium diisopropylamine (2.0 M inheptanes/THF/ethylbenzene) (2.5 ml, 5.1 mmol) diluted with THF (10 mL)under argon was cooled to −78° C. Chlorotrimethylsilane (2.5 mL, 19.5mmol) was added followed by 3,3-dimethyldihydro-2H-pyran-4(3H)-one(compound 449.1, 500 mg, 3.9 mmol) in THF (5 mL) and triethylamine (8.0mL, 57 mmol). The resulting mixture was stirred at −78° C. for 5 minutesand then quenched with saturated NaHCO₃ (20 mL). The mixture wasextracted with ether (30 mL) and the organics was washed with 1M citricacid (50 mL), dried (K₂CO₃), filtered and concentrated in vacuo. Theresidue was dissolved in THF (5 mL) and cooled to 0° C.N-Bromosuccinimide (694 mg, 3.9 mmol) was added and the resultingmixture was stirred at room temperature for 2 hrs and then quenched withsaturated NaHCO₃ (10 mL). The mixture was extracted with ether (2×20 mL)and the organics was washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (8% ethyl acetate in hexane) to yield the title compoundas an oil (150 mg, 18%).

Compound 449.3. Methyl5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoate.A mixture of 5-bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound449.2, 150 mg, 0.72 mmol), methyl 5-carbamimidoyl-2,4-dimethylbenzoatehydrochloride (compound 2.5, 135 mg, 0.55 mmol), and potassium carbonate(228 mg, 1.65 mmol) in acetonitrile (8 mL) was heated at 100° C. for 48hrs. The mixture was concentrated in vacuo and the residue was dissolvedin ethyl acetate (10 mL) and washed with brine (20 mL), dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (50% ethyl acetate in hexanes) to yield the titlecompound as a white solid (27 mg, 15%).

Compound 449.4,5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoicacid. To methyl5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoate(compound 449.3, 27 mg, 0.086 mmol) in THF (3 mL) was added 2 M lithiumhydroxide (430 μl, 0.86 mmol) and the mixture was heated at 50° C. for16 hrs. The volatile solvents were removed in vacuo and the resultingresidue was neutralized with 2M HCl to pH=3 and concentrated in vacuo togive a white solid and used in the next reaction without doing furtherpurification. m/z (ES−) 299 (M−H)⁻.

Compound 449.4-(1-(5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.Crude5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoicacid (compound 449.4, 0.086 mmol) was dissolved in DMF (1 mL).4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 19 mg, 0.086mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (HBTU) (65 mg, 0.17 mmol) and DIEA (45 μl, 0.26mmol) were added and the mixture was stirred at room temperature for 16hrs. The mixture was then diluted with ethyl acetate (10 mL) and washedwith brine (10 mL), dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (ethyl acetate) toobtain the title compound as a solid foam (15 mg, 30%). m/z (ES+) 469(M+H)⁺.

Compound 450.4-(1-(2,4-Dimethyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 449,except 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1) was used inplace of 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z(ES+) 455 (M+H)⁺.

Compound 451.1 and compound 451.2. tert-Butyl3-methyl-4-oxopiperidine-1-carboxylate and tert-butyl3,3-dimethyl-4-oxopiperidine4-carboxylate. Sodium hydride (60% inmineral oil) (1.27 g, 31.8 mmoL), was suspended in THF (80 mL) under anatmosphere of nitrogen. tert-Butyl 4-oxopiperidine-1-carboxylate (6.0 g,30 mmol) was added portion-wise at room temperature. The mixture wasstirred at room temperature for 1.5 hours and then methyl iodide (3.8mL, 6.1 mmol) was added. The mixture was stirred at room temperatureovernight and then cooled to 0° C. and carefully quenched with water (20mL). The mixture was extracted with ethyl acetate (100 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waspurified by silica gel chromatography (10:1 hexane/ethyl acetate) toobtain compound 451.1 as a clear oil (1.7 g, 27%) and compound 451.2. asa crystalline solid (963 mg, 14%).

Compound 451.3. tert-Butyl5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate. tert-Butyl3,3-dimethyl-4-oxopiperidine-1-carboxylate (0.963 g, 4.24 mmol) asdissolved in THF (10 mL) and then phenyltrimethylammonium tribromide(PTAT) (1.59 g, 424 mmol) was added. The mixture was stirred at roomtemperature for 2 hours then water (20 mL) was added and mixture wasextracted with ethyl acetate (100 mL). The organics was dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product was purified bysilica gel chromatography (10:1 hexane/ethyl acetate) to obtain compound451.3 as a white crystalline solid (0.94 g, 73%).

Compound 451.4-(4-(5-(5-Acetyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)cyclohexyl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except tert-butyl 5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate(compound 451.3) was used in place of tert-butyl3-bromo-4-oxopiperidine-1-carboxylate. m/z (ES+) 510 (M+H)⁺.

Compound 452.4-(1-(5-(5-Isopropyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.4-(1-(5-(7,7-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(0.12 g, 0.26 mmol) (intermediate prepared in the synthesis of compound451), DMF (4 mL), acetic acid (69 μL, 1.21 mmol), sodiumtriacetoxyborohydide (0.11 g, 0.52 mmol) and acetone (0.50 mL, 6.8 mmol)were mixed and stirred at room temperature for 2 hours. The reaction wascarefully quenched with water (10 mL) and the mixture was extracted withethyl acetate (60 mL) and the organics was dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by preparative TLC(DCM/10% MeOH) followed by a second preparative TLC (ethyl acetate/5%MeOH) to obtain the title compound as a white powder (4.1 mg, 8.1%). m/z(ES+) 510 (M+H)⁺.

Compound 454.1. Phenyl 4-methoxy-2-methylpyridine-1(2H)-carboxylate. A3-L four neck round-bottom flask was purged and maintained with anitrogen atmosphere and a solution of 4-methoxypyridine (30.0 g, 275mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) was added. The mixture wascooled to −40° C. and phenyl chloroformate (45.0 g, 287 mmol, 1.05equiv) was added dropwise. The resulting solution was stirred for 1 h at−40° C., then methylmagnesium bromide (3M, 110 mL, 1.20 equiv) was addedto the reaction mixture while maintaining the temperature at −40° C. Theresulting solution was warmed slowly to 5-10° C. and stirred for 2 h,then carefully quenched with ice water (100 mL). The resulting mixturewas extracted with ethyl acetate (2×1 L) and the combined organics waswashed with brine (1×300 mL), dried (Na₂SO₄), filtered and concentratedin vacuo to yield the title compound as a light brown oil (71.0 g,>theoretical).

Compound 454.2. tert-Butyl2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate. A 3-L four neckround-bottom flask was purged and maintained with a nitrogen atmosphereand a solution of phenyl 4-methoxy-2-methylpyridine-1(2H)-carboxylate(454.1, 70.0 g, 285 mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) wasadded. The solution was cooled to −78° C. then potassium tert-butoxide(128 g, 1.14 mol, 4.00 equiv) was added portion-wise. The resultingmixture was stirred at 10-15° C. for 20 h then concentrated in vacuo.The residue was dissolved in EtOAc (1.5 L), then carefully quenched withice water (200 mL). The layers were separated and the aqueous wasextracted with additional ethyl acetate (100 mL). The combined organicswas washed with aqueous sodium hydroxide (1.5 M, 3×100 mL), aqueoushydrochloric acid (1 M, 2×100 mL), and brine (200 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (ethyl acetate/petroleum ether, 1:200-1:20) as theeluent to obtain the title compound as a light yellow oil (31.0 g, 51%).

Compound 453.1 and compound 454.3. tert-Butyl6-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(453.1) and tert-butyl2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(454.3). A 500-mL three neck round-bottom flask was purged andmaintained with a nitrogen atmosphere and a solution of tert-butyl2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (compound 454.2,10.5 g, 49.5 mmol, 1.00 equiv) in tetrahydrofuran (300 mL) was added.The solution was cooled to −78° C. and L-Selectride (1 M in THF, 60 mL,1.20 equiv) as added drop-wise. The resulting solution was stirred for 2h at −78° C. then chlorotrimethylsilane (6.96 g, 64.1 mmol, 1.30 equiv)was added drop-wise with stirring. The resulting solution was stirredfor 16 h at 10-15° C., and then concentrated in vacuo. The residue wasdiluted with n-hexane (500 mL) and the solids were filtered away. Thefiltrate was concentrated in vacuo and the residue purified by silicagel chromatography ethyl acetate/petroleum ether (1:100-1:20) as theeluent to obtain a mixture of the title compounds as a light yellowsolid (10.0 g, 71%).

Compound 453.2 and compound 454.4. tert-Butyl5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (453.2) and tert-butyl3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (454.4). Into around-bottom flask, was placed a solution of a mixture of tert-butyl6-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2-carboxylate andtert-butyl2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(compound 453.1 and compound 454.2, 4.00 g, 12.5 mmol, 1.00 equiv, 89%combined purity) in tetrahydrofuran (250 mL). The mixture was cooled to0-5° C. and N-bromosuccinimide (4.97 g, 27.9 mmol, 2.2 equiv) was addedto the reaction mixture in portions. The resulting mixture was stirredat 25° C. for 2 h, then concentrated in vacuo. The residue was purifiedby silica gel chromatography with ethyl acetate/petroleum ether(1:100-1:10) as the eluent to obtain a mixture of the title compounds asa yellow oil (2.50 g, 69%).

Compound 453.3 and compound 454.5.5-(5-(tert-Butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid (453.3) and5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid (454.5). Into a 50-mL sealed tube, was placed a solution of amixture of tert-Butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate andtert-butyl 3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound453.2 and compound 454.4, 1.60 g, 5.48 mmol, 1.00 equiv) inN,N-dimethylformamide (10 mL). 5-Formyl-2,4-dimethylbenzoic acid(compound 16.3, 978 mg, 5.49 mmol, 1.00 equiv), ammonium acetate (1.90g, 24.7 mmol, 4.50 equiv), and ammonium hydroxide (2.88 g, 16.4 mmol,3.00 equiv, 20%) were added and the resulting mixture was stirred for 2h at 130° C. The mixture was cooled to 10-15° C. then quenched with icewater (50 mL). The resulting solution was extracted with ethyl acetate(2×50 mL) and the organics were combined. The pH of the aqueous wasadjusted to 6 with hydrogen chloride (2 M) and extracted with ethylacetate (2×150 mL) and all organic extracts were combined, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography with ethyl acetate/petroleum ether(1:4-2:1) as the eluent to obtain a mixture of the title compounds as alight yellow oil (480 mg, 23%).

Compound 453.4 and compound 454.6. tert-Butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 453.4) and tert-butyl2-5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 454.6). Into around-bottom flask, was placed a solution of amixture of5-(5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid and5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid (compound 453.3 and compound 454.5, 480 mg, 1.25 mmol, 1.00 equiv)in N,N-dimethylformamide (10 mL). DIEA (643 mg, 4.98 mmol, 4.00 equiv),EDC (476 mg, 2.48 mmol, 2.00 equiv), and 1-hydroxybenzotrizole (337 mg,2.50 mmol, 2.00 equiv) were added and the resulting solution was stirredat 25° C. for 20 min. 4-(Piperidin-4-yl)benzonitrile hydrochloride(compound 1.5, 276 mg, 1.24 mmol, 1.00 equiv) was then added in portionsat 0° C. The resulting solution was stirred at 25° C. for 16 h, and thenquenched with of ice water (40 mL). The resulting solids were collectedby filtration, and then dissolved in ethyl acetate (100 mL). Theresulting organics was washed with brine (2×30 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to obtain a mixture of the titlecompounds as a light yellow oil (440 mg, 64%).

Compound 453.5 and compound 454.7.4-(1-(2,4-Dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate (compound 453.5) and4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate (compound 454.7). Into around-bottom flask, wasplaced a solution of a mixture of tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylateand tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 453.4 and compound 454.6, 440 mg, 0.790 mmol, 1.00 equiv) indichloromethane (10 mL) and trifluoroacetic acid (3 mL). The resultingsolution was stirred at 25° C. for 20 h, then concentrated in vacuo toobtain a mixture of the title compounds as a yellow oil (450 mg, 99%).

Compounds 453 and 454. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 453) and methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 454).Into an 8-mL sealed tube, was placed a mixture of4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate and4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate (compound 453.5 and compound 454.7, 100 mg, 0.176mmol, 1.00 equiv) in dichloromethane (6 mL). DIEA (114 mg, 0.880 mmol,5.00 equiv) was added and the mixture was cooled to 0° C. Dimethyldicarbonate (29.6 mg, 0.220 mmol, 1.25 equiv) was added drop-wise withstirring at 0° C., and then the resulting solution was stirred for 2.5 hat 0-5° C. The resulting mixture was concentrated in vacuo and theresidue was purified by prep-HPLC (1#-Pre-HPLC-001 (SHIMADZU)): Column,Xbridge Prep C18, 5 um, 1.9*150 mm; mobile phase, water with 0.03%NH₃H₂O and CH₃CN (39.0% CH₃CN up to 52.0% in 7 min, up to 100.0% in 1min, down to 39.0% in 1 min); Detector, Waters 2489 254 & 220 nm. Thetitle compounds were obtained from the prep-HPLC as a mixture of isomers(30 mg). The isomeric mixture was purified by chiral-prep-HPLC(2#-Gilson Gx 281 (HPLC-09)): Column, Chiralpak IA, 2*25 cm, 5 um;mobile phase, Hex (0.1% DEA) and ethanol (0.2% TEA) (hold 50.0% ethanol(0.2% TEA) in 10 min); Detector, UV 220/254 nm. The chiral-prep-HPLCfractions containing pure, separated products were appropriatelycombined and lyophilized to obtain methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 453) as a white solid (14.2 mg, 13%) and methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 454) as white solid (11.8 mg, 10%), Compound 453: m/z (ES+)512 (M+H)⁺. Compound 454: m/z (ES+) 512 (M+H)⁺.

Compounds 455 & 456.4-(1-(5-(5,6-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 455) and4-(1-(5-(4,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 456). Into a 10-mL sealed tube, was placed a solution of amixture of4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitriletrifluoroacetate and4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitriletrifluoroacetate (compound 453.5 and compound 454.7, (100 mg, 0.22 mmol,1.00 equiv) in tetrahydrofuran (5 mL). Formaldehyde (1 mL, 37 wt %) andsodium triacetoxyborohydride (162 mg, 0.760 mmol, 3.5 equiv) were addedto the mixture and stirred for 2.5 h at 40° C. The mixture wasconcentrated in vacuo and the residue was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, Xbridge PrepC18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN(32% CH3CN up to 42% in 8 min, up to 100% in 2 min, down to 32% in 1min); Detector, Waters 2489 254 nm & 220 nm. The title compounds wereobtained from the prep-HPLC as a mixture of isomers (50 mg). Theisomeric mixture was purified by chiral-prep-HPLC with the followingconditions (2#-Gilson Gx 281 (HPLC-09)): Column, Chiralpak IC, 2*25 cm,5 um; mobile phase, Hex (0.2% TEA) and ethanol (0.2% TEA) (hold 50.0%ethanol (0.2% TEA) in 27 min); Detector, UV 220/254 nm. Thechiral-prep-HPLC fractions containing pure, separated products wereappropriately combined and lyophilized to obtain4-(1-(5-(5,6-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 455) as a white solid (13.5 mg, 13%) and4-(1-(5-(1,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 456) as a white solid (6.8 mg, 7%). Compound 455: m/z (ES+)468 (M+H)⁺. Compound 456: m/z (ES+) 468 (M+H)⁺.

Compound 457.1 and compound 457.2. tert-Butyl3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound 457.1) andtert-butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound457.2). Into a 1-L four neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol,1.00 equiv) in ether (700 mL). Ammonium acetate (904 mg, 11.7 mmol, 0.50equiv) and azobisisobutyronitrile (AIBN) (192 mg, 1.17 mmol, 0.05 equiv)were added. The mixture was cooled to 0° C., then N-bromosuccinimide(4.15 g. 23.5 mmol, 1.00 equiv) was added in portions. The resultingmixture was stirred for 4 h at 25° C., then concentrated in vacuo. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:100-1:10) as the eluent to obtain a mixtureof the title compounds as a light yellow oil (4.10 g, 60%).

Compound 457.4-(1-(5-(5-Acetyl-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 400and compound 2, except a mixture of tert-butyl3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound 457.1) andtert-butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound457.2) was used in place of 3-bromo-5-methyldihydro-2H-pyran-4(3H)-one(compound 400.2). The product contains about 10% of the other methylregioisomer4-(1-(5-(5-acetyl-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.m/z (ES+) 496 (M+H)⁺.

Compound 458.4-(1-(5-(5′-Acetyl-3′,4′,5′,6′-tetrahydrospiro[cyclopropane-1,7′-imidazo[4,5-c]pyridin]-2′-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 449and compound 2, except tert-butyl8-oxo-5-azaspiro[2.5]octane-5-carboxylate (Remen, L. et al. Bioorg. andMed. Chem. Lett., 2009, 32, 351-357) was used in place of3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z (ES+) 508(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.71 (d, J=8.1 Hz, 2H), 7.47 (d,J=7.8 Hz, 2H), 7.37-7.20 (m, 2H), 4.77 and 4.71 (2 singlets, acetylamide rotamers, CH₂, 2H), 3.77 and 3.72 ((2 singlets, acetyl amiderotamers, CH₂, 2H), 3.71-3.67 (m, 1H), 3.30-3.18 (m, 1H), 2.99 (t,J=11.6 Hz, 2H), 2.48-2.27 (m, 6H), 2.24 and 2.21 (2 singlets, acetylamide rotamers, acetyl CH₃, 3H), 2.10-1.95 (m, 1H), 1.92-1.52 (m, 3H),1.18-0.96 (m, 4H).

Compound 459.4-(1-(5-(6-Methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound449, except 4-methoxycyclohexanone (Kaiho, T. et al., J. Med. Chem,1989, 32, 351-357) was used in place of3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z (ES+) 469(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.69 (d, J=8.1 Hz, 2H), 7.53-7.44 (m,2H), 7.37-7.21 (m, 2H), one proton estimated under methanol (1H),3.84-3.75 (m, 1H), 3.73-3.57 (m, 1H), 3.45 (s, 3H), 3.27-3.19 (m, 1H),3.05-2.91 (m, 3H), 2.79-2.58 (m, 3H), 2.46 (s, 3H), 2.40 and 2.29 (2singlets, amide rotamers, 3H), 2.17-1.92 (m, 3H), 1.92-1.67 (m, 3H).

Compound 460.4-(1-(5-(6-Hydroxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, was placed a solution of4-(1-(5-(6-methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 459, 80 mg, 0.17 mmol, 1.0 equiv) in a solvent mixture ofacetonitrile and dichloromethane (10/10 mL). Tetrachlorosilane (32 mg,0.19 mmol, 1.1 equiv) and sodium iodide (28 mg, 0.19 mmol, 1.1 equiv)were added to the reaction and the resulting mixture was stirredovernight at 20° C. The reaction was quenched with aqueous sodiumbicarbonate (10 mL) and the aqueous was extracted with ethyl acetate(3×10 mL). The combined organics was dried (Na₂SO₄), filtered andconcentrated in vacuo and the residue was purified by silica gelchromatography with ethyl acetate as the eluent to obtain the titlecompound as a yellow solid (7.1 mg, 9%). m/z (ES+) 455 (M+H)⁻.

Compound 461.1. 4-Methoxyhepta-1,6-diene. Into a round-bottom flask, wasplaced a solution of hepta-1,6-dien-4-ol (2.00 g, 17.8 mmol, 1.00 equiv)and iodomethane (5.00 g, 35.2 mmol, 2.00 equiv) in tetrahydrofuran (30mL). The solution was cooled to 0° C. and sodium hydride (1.00 g, 25.0mmol, 1.50 equiv, 60% in mineral oil) was added to the reaction inportions. The resulting mixture was stirred overnight at roomtemperature, then carefully quenched with water (5 mL) and diluted withof ether (30 mL). The organics was washed with brine (2×20 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to obtain the titlecompound as a colorless oil (2.00 g, 84%).

Compound 461.2. 4-Methoxycyclopent-1-ene. Into around-bottom flask,which was purged and maintained with an inert atmosphere of nitrogen,was placed a solution of 4-methoxyhepta-1,6-diene (compound 461.1, 200mg, 1.43 mmol, 1.00 equiv, 90%) in dichloromethane (25 mL). Grubbs IIcatalyst (55 mg, 0.06 mmol, 0.04 equiv) was added and the resultingsolution was stirred overnight at room temperature. The mixture wasconcentrated in vacuo to obtain the title compound as a colorless oil(100 mg, 57%).

Compound 461.3. 2-Bromo-4-methoxycyclopentanol. Into a round-bottomflask, was added a solution of 4-methoxycyclopent-1-ene (compound 461.2,1.00 g, 8.66 mmol, 1.00 equiv, 85%) in dichloromethane (100 mL) and asolution of N-bromosuccinimide (2.00 g, 11.3 mmol, 1.00 equiv) in water(20 mL). The reaction mixture was stirred at room temperature for 3hours and then the resulting mixture was washed with water (20 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to obtain the titlecompound as a colorless oil (1.00 g, 36%).

Compound 461.4. 2-Bromo-4-methoxycyclopentanone. Into a round-bottomflask, was placed a solution of 2-Bromo-4-methoxycyclopentanol (compound461.3, 1.00 g, 3.08 mmol, 1.00 equiv, 60%) in dichloromethane (100 mL).Dess-Martin periodinane (2.00 g, 4.72 mmol, 1.10 equiv) was added inportions and the mixture was stirred overnight at room temperature. Themixture was then diluted with water (20 mL) and quenched with Na₂S₂O₄ (4g). The aqueous was extracted with dichloromethane (100 mL) and thecombined organics was washed with brine (30 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to obtain the title compound as abrown oil (800 mg, 81%).

Compound 461.5. Methyl5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate.Into around-bottom flask, was placed a solution of2-bromo-4-methoxyclopentanone (compound 461.4, 600 mg, 1.86 mmol, 60%)in ACN (15 mL). Methyl 5-carbamimidoyl-2,4-dimethylbenzoatehydrochloride (compound 2.5, 320 mg) and potassium carbonate (430 mg,3.11 mmol) were added and the mixture was stirred overnight at 80° C.The mixture was concentrated in vacuo and the residue was diluted withethyl acetate (50 mL) and then washed with brine (2×20 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography with dichloromethane/methanol (10:1) as theeluent to obtain the title compound as a brown oil (200 mg, 27%).

Compound 461.6. Methyl5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate.Into around-bottom flask, was placed a solution of methyl5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate(compound 461.5, 200 mg, 0.38 mmol, 1.00 equiv, 60%) inN,N-dimethylformamide (mL). p-Toluenesulfonic acid (20 mg, 0.12 mmol,0.18 equiv) was added and the resulting solution was stirred overnightat 80° C., then concentrated in vacuo. The residue was purified bysilica gel chromatography with dichloromethane/methanol (10:1) as theeluent to obtain the title compound as a brown oil (100 mg, 66%).

Compound 461.7.5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoicacid. Into around-bottom flask, was placed a solution of methyl5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate(compound 461.6, 100 mg, 0.270 mmol, 1.00 equiv, 80%) in methanol (3mL). A solution of sodium hydroxide (67.0 mg, 1.68 mmol, 5.00 equiv) inwater (3 mL) was added and the resulting mixture was stirred overnightat 70° C., then concentrated in vacuo. The residue was diluted withwater (3 mL) and the pH of the solution was adjusted to 2-3 with aqueoushydrogen chloride (12 M). The mixture was extracted ethyl acetate (3×10mL), and the combined organics was concentrated in vacuo to obtain thetitle compound as a brown solid (80 mg, 84%).

Compound 461.4-(1-(5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, was placed a solution of5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoicacid (compound 461.7, 60 mg, 0.17 mmol, 1.00 equiv, 80%) inN,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 46 mg, 0.20 mmol, 1.00 equiv),4-dimethylaminopyridine (52 mg, 0.43 mmol, 2.00 equiv), and EDC.HCl (80mg, 0.42. mmol, 2.00 equiv) were added and the mixture was stirredovernight at room temperature. The resulting solution was diluted withethyl acetate (30 mL) and washed with brine (3×10 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue (40 mg) was purified bypreparative-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase,water with 0.05% TFA and CH₃CN (15.0% CH₃CN up to 55.0% in 7 min, up to100.0% in 1 min, down to 15.0% in 1 min); Detector, Waters 2489 254 &220 nm. The fractions containing pure product were combined andlyophilized to obtain the title compound as a white solid (8.9 mg, 11%).m/z (ES+) 455 (M+H)⁻.

Compound 462.1. 5-Bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one. Intoaround-bottom flask, was placed a solution of 2,2-dimethyloxan-4-one(1.00 g, 7.80 mmol, 1.00 equiv) in ether (20 mL). N-Bromosuccinimide(1.50 g, 25.5 mmol, 3.26 equiv) was added in portions, followed by theaddition of ammonium acetate (60.0 mg, 0.78 mmol, 0.10 equiv). Theresulting mixture was stirred overnight at 25° C., then diluted withethyl acetate (20 mL). The resulting mixture was washed brine (2×40 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:30) as the eluent to obtain the title compound as a yellow oil (508mg, 31%).

Compound 462.4-(1-(5-(6,6-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound461, except 5-bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one (compound462.1) was used in place of 2-bromo-4-methoxycyclopentanone (compound461.4). m/z (ES+) 469 (M+H)⁺.

Compound 463.1. Trimethyl((4-(trimethylsilyl)but-3-yn-1-yl)oxy)silane.Into a 1-L three neck round-bottom flask, was placed a solution ofbut-3-yn-1-ol (20.0 g, 285 mmol, 1.00 equiv) in tetrahydrofuran (300 mL)and the mixture was purged with nitrogen. The mixture was cooled to −78°C., then n-butyllithium (2.5 M in THF) (270 mL, 2.40 equiv) was addeddrop-wise followed by the addition of chlorotrimethylsilane (67.9 g, 625mmol, 2.20 equiv). The resulting mixture was then stirred for 1 h at 25°C. then carefully quenched with aqueous sodium bicarbonate (250 mL). Theaqueous was extracted with ether (3×100 mL) and the combined organicswas dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography with ether/petroleum ether(1:10-1:1) as the eluent to obtain the title compound as a colorless oil(10.0 g, 16%).

Compound 463.2. Trimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane.Into a round-bottom flask, was placed a solution of compound 463.1, 2.00g, 7.46 mmol, 1.00 equiv, 80%) in hexane (30 mL). The system was purgedwith nitrogen. Quinoline (0.1 mL, 0.10 equiv) and Lindlar reagent(poisoned by Pb) (0.2 g, 0.10 equiv, 5%) were added to the mixture. Theresulting mixture was hydrogenated overnight at room temperature underatmosphere pressure of hydrogen. After completion of the reaction, thesystem was purged with nitrogen and the solids were removed byfiltration. The filtrate was concentrated in vacuo and the residue waspurified by silica gel chromatography with hexane/ether (20:1) as theeluent to obtain the title compound as a colorless oil (1.50 g, 74%).

Compound 463.3. 6-Methyl-3,6-dihydro-2H-pyran. Into around-bottom flask,was placed a mixture oftrimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane (compound 463.2,1.50 g, 6.93 mmol, 1.00 equiv), acetaldehyde (900 mg, 20.4 mmol. 3.00equiv), and indium(III) chloride (1.50 g, 1.00 equiv) in dichloromethane(15 mL). The resulting mixture was stirred overnight at 25° C., thendiluted with DCM (50 mL). The organics was washed with brine (3×20 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to obtain the titlecompound as a brown oil (0.600 g, 88%).

Compound 463.4 and compound 463.5.4-Bromo-2-methyldihydro-2H-pyran-3(4H)-one (compound 463.4) and3-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 463.5). Into around-bottom flask, was placed a solution of o-iodoxybenzoic acid (IBX)(3.42 g, 6.11 mmol, 2.00 equiv) in DMSO (12 mL). The mixture was stirredfor 30 min at 25° C. then a solution of 6-methyl-3,6-dihydro-2H-pyran(compound 463.3, 600 mg, 4.28 mmol, 1.00 equiv, 70%) in dichloromethane(30 mL) was added drop-wise. The mixture was cooled to 0-5° C., thenN-bromosuccinimide (1.20 g, 6.74 mmol, 1.10 equiv) was addedportion-wise. The resulting mixture was stirred overnight at 25° C.,then the solids were removed by filtration. The filtrate was dilutedwith dichloromethane (50 mL) and washed with brine (3×20 mL). Themixture was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:20) as the eluent to obtain a mixture of thetitle compounds as a brown oil (600 mg, 73%).

Compound 463.4-(1-(2,4-Dimethyl-5-(4-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound461, except a mixture of 4-bromo-2-methyldihydro-2H-pyran-3(4H)-one(compound 463.4) and 3-bromo-2-methyldihydro-2H-pyran-4(3H)-one(compound 463.5) was used in place of 2-bromo-4-methoxycyclopentanone(compound 461.4). m/z (ES+) 455 (M+H)⁺.

Compound 464.1. 4-(Allyloxy)pent-1-ene. A 500-mL four neck round-bottomflask was purged and maintained with an inert atmosphere of nitrogen,then a suspension of sodium hydride (14.0 g, 350 mmol, 2.01 equiv, 60%)in N,N-dimethylformamide (100 mL) was added. The mixture was cooled to0° C., then a solution of pent-4-en-2-ol (15.0 g, 174 mmol, 1.00 equiv)in N,N-dimethylformamide (100 mL) was added drop-wise and the mixturewas stirred for 20 min at 0° C. The mixture was cooled to −20° C. and asolution of 3-bromoprop-1-ene (20.9 g, 172 mmol, 0.99 equiv) inN,N-dimethylformamide (100 mL) was added. The resulting mixture wasallowed to warm to room temperature and stirred overnight, thencarefully quenched with H₂O (500 mL). The aqueous was extracted withethyl acetate (4×100 mL) and the combined organics was washed with brine(2×200 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to obtainthe title compound as a yellow oil (13.3 g, 61%).

Compound 464.2. 2-Methyl-3,6-dihydro-2H-pyran. A 500-mL three neckround-bottom flask was purged and maintained with an inert atmosphere ofnitrogen, then a solution of 4-(allyloxy)pent-1-ene (compound 464.1,3.00 g, 23.8 mmol, 1.00 equiv) DCE (200 mL) was added. Grubbs catalystwas added (810 mg, 0.950 mmol, 0.04 equiv) and the mixture was stirredat 60° C. for 4 h. The mixture was then concentrated in vacuo at 20° C.to obtain the title compound as a colorless oil (2.00 g, 86%).

Compound 464.3 and 464.4. 4-Bromo-6-methyltetrahydro-2H-pyran-3-ol and5-bromo-2-methyltetrahydro-2H-pyran-4-ol. Into a round-bottom flask, wasplaced a solution of methyl-3,6-dihydro-2H-pyran (compound 464.2, 2.00g, 20.4 mmol, 1.00 equiv) in a mixture of tetrahydrofuran and H₂O (20/20mL). N-Bromosuccinimide (3.60 g, 20.3 mmol, 1.00 equiv) was added andthe resulting mixture was stirred at room temperature overnight. Themixture was extracted with dichloromethane (2×20 mL) and the combinedorganics were washed with brine (2×20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo to obtain a mixture of the title compounds as ayellow oil (1.10 g, crude).

Compound 464.5 and 464.6. 4-Bromo-6-methyldihydro-2H-pyran-3(4H)-one and5-bromo-2-methyldihydro-2H-pyran-4(3H)-one. Into around-bottom flask,was placed a mixture of 4-bromo-6-methyltetrahydro-2H-pyran-3-ol(compound 464.3) and 5-bromo-2-methyltetrahydro-2H-pyran-4-ol (compound464.4) (1.10 g, 5.64 mmol, 1.00 equiv) as a solution in dichloromethane(30 mL). Dess-Martin periodinane (2.90 g, 6.84 mmol, 1.21 equiv) wasadded and the resulting solution was stirred overnight at roomtemperature, then quenched with water (20 mL). The aqueous was extractedwith dichloromethane (2×20 mL) and the combined organics were washedwith brine (2×50 mL), dried (Na₂SO₄), filtered and concentrated in vacuoto obtain a mixture of the title compounds as a yellow oil (0.7 g).

Compound 464.7. Methyl2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate.Into around-bottom flask, was placed a mixture of4-bromo-6-methyldihydro-2H-pyran-3(4H)-one (compound 464.5) and5-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 464.6) (700 mg,3.63 mmol) as a solution in acetonitrile (20 mL). Methyl5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 750mg) and potassium carbonate (1.00 g, 7.25 mmol) were added and themixture was stirred overnight at 75° C. under nitrogen. The mixture wascooled and the solids were removed by filtration. The filtrate wasconcentrated in vacuo and the residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1:1) as the eluent toobtain the title compound as a yellow solid (100 mg, 9%).

Compound 464.8.2,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoicacid. Into around-bottom flask, was placed a solution of methyl2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate(compound 464.7, 100 mg, 0.330 mmol, 1.00 equiv) in methanol (10 mL). Asolution of lithium hydroxide (76 mg, 3.17 mmol, 10.0 equiv) water (10mL) was added and the resulting solution was stirred for 4 h at roomtemperature. The mixture was concentrated in vacuo and then aqueous HClwas added until the pH was 5-6. The mixture was adjusted to pH 5-6 withaqueous HCl and then the resulting mixture was concentrated in vacuo.MeOH (5 mL) was added to the residue and the solids were removed byfiltration. The filtrate was concentrated in vacuo to obtain the titlecompound as a yellow solid (60 mg, 63%).

Compound 464. 4-(1-(2,4-Dimethyl -5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, was placed a solution of2,4-dimethyl-5-[6-methyl-3H,4H,6H,7H-pyrano[3,4-d]imidazol-2-yl]benzoicacid (50 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL).EDC.HCl (67 mg, 0.35 mmol, 2.00 equiv), 4-dimethylaminopyridine (64 mg,0.52 mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.5, 39 mg, 0.18 mmol, 1.00 equiv) were added and the solutionwas stirred for 2 h at room temperature. The reaction was quenched withwater (20 mL) and the aqueous was extracted with ethyl acetate (2×20mL). The combined organics was dried (Na₂SO₄), filtered and concentratedin vacuo. The residue was purified by silica gel chromatography withethyl acetate/petroleum ether (1:1) as the eluent. The crude product (20mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, Xbridge Prep Phenyl, 5 um, 19*150mm; mobile phase, water with 0.03% NH₃H₂O and CH₃CN (30% CH₃CN up to 60%in 9 min, up to 100% in 1 min, down to 30% in 1 min); Detector, Waters2489 254 nm & 220 nm. The fractions containing pure product werecombined and lyophilized to obtain the title compound as a white solid(8.0 mg, 10%). m/z (ES+) 455 (M+H)⁺.

Compound 465.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carbonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound461, except cyclopent-3-enecarbonitrile (Johnson, C. R. et al. J. Org.Chem, 1969, 34, 860-864) was used in place of 4-methoxycyclopent-1-ene(compound 461.2). m/z (ES+) 450 (M+H)⁺.

Compound 466.1. Tetrahydrofuran-3,4-diyl dimethanesulfonate. Into around-bottom flask, was placed a solution of tetrahydrofuran-3,4-diol(500 mg, 480 mmol, 1.00 equiv) and triethylamine (1.45 g, 14.3 mmol,3.00 equiv) in dichloromethane (8 mL). The mixture was cooled to 0-5° C.and a solution of methanesulfonyl chloride (1.40 g, 12.2 mmol, 2.50equiv) in dichloromethane (2 mL) was added drop-wise. The solution wasstirred at room temperature for 2 h, and then diluted withdichloromethane (100 mL). The solution was washed with aqueous NH₄Cl(2×30 mL) then brine (30 mL), dried (Na₂SO₄), filtered and concentratedin vacuum to obtain the title compound as a brown solid (1.00 g, 72%).

Compound 466.2. 3,4-Diazidotetrahydrofuran. Into a round-bottom flask,was placed a mixture of tetrahydrofuran-3,4-diyl dimethanesulfonate(compound 466.1, 2.00 g, 7.30 mmol, 1.00 equiv, 95%) and sodium azide(4.00 g, 61.5 mmol, 8.00 equiv) in N,N-dimethylformamide (20 mL). Theresulting mixture was stirred overnight at 100° C. behind a blastshield, then cooled and diluted with ether (100 mL). The mixture waswashed with brine (5×20 mL), dried (Na₂SO₄), filtered and concentratedin vacuo to obtain the title compound as a colorless oil (1.00 g, 80%).

Compound 466.3. Tetrahydrofuran-3,4-diamine. Into around-bottom flask,was placed a solution of 3,4-diazidotetrahydrofuran (compound 466.2, 900mg, 5.26 mmol, 1.00 equiv, 90%) in ethanol (10 mL). The system waspurged with nitrogen and palladium on carbon (10 wt % Pd) (900 mg) wasadded. After further purging the system with nitrogen, the atmospherewas changed to hydrogen and the resulting suspension was stirredovernight at room temperature under an atmosphere of hydrogen. Afterpurging the system with nitrogen, the solids were removed by filtrationand the filtrate was concentrated in vacuo to obtain the title compoundas a colorless oil (600 mg, 98%).

Compound 466.4. Methyl 5-(imino(methoxy)methyl)-2,4-dimethylbenzoatehydrochloride. Into a 50-mL three neck round-bottom flask, was placed asolution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 900 mg,4.28 mmol, 1.00 equiv, 90%) in methanol (20 mL). Hydrogen chloride gaswas introduced by bubbling through the solution for 0.5 hr. The reactionmixture was then transferred into a 30-mL sealed tube and stirredovernight at room temperature. The mixture was concentrated under vacuumand the residue was diluted with ethyl acetate (30 mL) and extractedwith water (10 mL). The aqueous was concentrated in vacuo to obtain thetitle compound as a white solid (200 mg, 15%).

Compound 466.5. Methyl2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate.Into around-bottom flask, was placed a solution oftetrahydrofuran-3,4-diamine (compound 466.3, 140 mg, 1.17 mmol, 1.00equiv, 85%) in ethanol (6 mL). Methyl5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride (compound466.4, 300 mg, 0.930 mmol, 1.00 equiv) and triethylamine (140 mg, 1.38mmol, 1.00 equiv) were added and the resulting solution was stirredovernight at 80° C., then concentrated in vacuo. The residue waspurified by silica gel chromatography with dichloromethane/methanol(10:1) as the eluent to obtain the title compound as a brown oil (120mg, 34%).

Compound 466.5.2,4-Dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoicacid. Into around-bottom flask, was placed a solution of methyl2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate(compound 466.5, 100 mg, 0.330 mmol, 1.00 equiv, 90%) and sodiumhydroxide (73 mg, 1.82 mmol, 5.00 equiv) in methanol/H₂O (3/3 mL). Theresulting solution was stirred overnight at 70° C., then concentrated invacuum. The residue was diluted with H₂O (5 mL) and the pH of thesolution was adjusted to 2-3 with hydrogen chloride (12 N), thenextracted with ethyl acetate (3×10 mL). The combined organics wasconcentrated in vacuo to obtain the title compound as a yellow solid(80.0 mg, 84%).

Compound 466.4-(1-(2,4-Dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, was placed a solution of2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoicacid (compound 466.5, 80.0 mg, 0.250 mmol, 1.00 equiv, 80%) inN,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 82.0 mg, 0.350 mmol, 1.20 equiv),4-dimethylaminopyridine (76.0 mg, 0.620 mmol, 2.00 equiv), and EDC.HCl(116 mg, 0.610 mmol, 2.00 equiv) were added and the resulting solutionwas stirred overnight at room temperature. The mixture was diluted withethyl acetate (30 mL) and washed with brine (3×15 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product (50 mg) waspurified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase,water with 0.05% TFA and CH₃CN (15% CH₃CN up to 50% in 9 min, up to 100%in 1 min, down to 15% in 1 min); Detector, Waters 2489 254 nm & 220 nm.The fractions containing pure product were combined and lyophilized toobtain the title compound as a white solid (13 mg, 12%). m/z (ES+) 429(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.70 (d, 2H), 7.53-7.36 (m, 4H), 5.09(s, 2H), 4.17 (d, J=10.8 Hz, 2H), 3.77 (d, J=10.5 Hz, 2H), 3.60-3.44 (m,1H), (m, partially overlapped with water, 1H), 3.10-2.92 (m, 2H), 2.48(s, 3H), 2.45 and 2.35 (2 singlets, amide rotamers, Ar—CH₃, 3H),2.10-1.97 (m, 1H), 1.92-1.52 (m, 3H).

Compound 467.4-(1-(4-Fluoro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1and compound 2, except 4-fluoro-2-methylbenzoic acid was used in placeof 2,4 dimethylbenzoic acid. m/z (ES+) 445 (M+H)⁺.

Compound 468.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chloro-2-methylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except 4-chloro-2-methylbenzoic acid was used in place of 2,4dimethylbenzoic acid. m/z (ES+) 502 (M+H)⁺.

Compound 469.1-(2-(2-Chloro-5-(4-(4-fluorophenyl)piperidine-1-carbonyl)-4-methylphenyl)-6,7-dihydro-311-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2and compound 468. m/z (ES+) 495 (M+H)⁺.

Compound 470.1. Methyl 2-bromo-4-fluorobenzoate. Into a round-bottomflask, was placed a solution of 2-bromo-4-fluorobenzoic acid (21.8 g,99.5 mmol, 1.00 equiv) in a solvent mixture of sulfuric acid (20 mL) andmethanol (20 mL). The resulting solution was stirred for 5 h at 85° C.,then cooled and cooled and concentrated in vacuo. The residue wasdiluted with ethyl acetate (200 mL) and washed with brine (200 mL) thenaqueous NaHCO₃ (100 mL. Note: gas evolution), dried (Na₂SO₄), filteredand concentrated in vacuo to obtain the title compound as a light yellowoil (22.0 g, 95%).

Compound 470.1. Methyl 2-ethyl-4-fluorobenzoate. The title compound(colorless oil, 14.5 g, 93%) was prepared using a procedure similar tothat used for the preparation of compound 48.1 and using of methyl2-bromo-4-fluorobenzoate (compound 470.1, 20.0 g) in place of methyl2-bromo-4-methylbenzoate.

Compound 470.4-(1-(2-Ethyl-4-fluoro-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1and compound 2, except methyl 2-ethyl-4-fluorobenzoate (compound 470.1)was used in place of 2,4-dimethylbenzoic acid, and4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.5). m/z (ES+) 477 (M+H)⁺.

Compound 471.1. 4-Chloro-5-iodo-2-methylbenzoic acid. The title compoundwas prepared using standard chemical manipulations and proceduressimilar to those used for the preparation of compound 2.1, except4-chloro-2-methylbenzoic acid was used in place of 2,4-dimethylbenzoicacid.

Compound 471.2. 4-Chloro-5-formyl-2-methylbenzoic acid. The titlecompound was prepared using standard chemical manipulations andprocedures similar to those used for the preparation of compound 392.2,except 4-chloro-5-iodo-2-methylbenzoic acid (compound 471.1) was used inplace of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 392.1).

Compound 471.4-(1-(4-Chloro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound400, except 4-chloro-5-formyl-2-methylbenzoic acid (compound 471.2) wasused in place of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4),3-bromodihydro-2H-pyran-4(3H)-one was used in place of3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2) and4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.5). m/z (ES+) 479 (M+H)⁺.

Compound 472.1. Methyl 4-chloro-2-ethyl-5-iodobenzoate. The titlecompound was prepared using standard chemical manipulations andprocedures similar to those used for the preparation of compound 211.2,except methyl 4-chloro-2-ethylbenzoate (compound 178.2) was used inplace of methyl 2-ethyl-4-methylbenzoate (compound 48.1).

Compound 472.2. 4-Chloro-2-ethyl-5-iodobenzoic acid. The title compoundwas prepared using standard chemical manipulations and proceduressimilar to those used for the preparation of compound 211.3, exceptmethyl 4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) was used inplace of 2-ethyl-5-iodo-4-methylbenzoate (compound 211.2).

Compound 472.4-(1-(4-Chloro-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound400, except 4-chloro-2-ethyl-5-iodobenzoic acid (compound 472.2) wasused in place of 2-ethyl-5-formyl-4-methylbenzoic acid (211.4),3-bromodihydro-2H-pyran-4(3H)-one was used in place of3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2) and4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.5). m/z (ES+) 493 (M+H)⁺.

Compound 473.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chloro-2-ethylbenzoyl)piperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except methyl 4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) was usedin place of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2). m/z (ES+)516 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.73-7.54 (m, 4H), 7.53-7.42 (m,2H), 4.75 and 4.70 (2 singlets, acetyl amide rotamers, CH₂, 2H),4.02-3.88 (m, 2H), 3.68-3.52 (m, 1H), 3.32-3.20 (m, 1H), 3.07-2.88 (m,3H), 2.88-2.58 (m, 3H), 2.25 and 2.22 (2 singlets, acetyl amiderotamers, acetyl CH₃, 3H). 2.11-1.98 (m, 1H), 1.93-1.53 (m, 3H),1.39-1.22 (m, 3H).

Additional example compounds are found in Table 1.

Example 1 FASN Inhibition by Compounds of the Present Disclosure

Determination of FASN biochemical activity: The FASN enzyme was isolatedfrom SKBr3 cells. SKBr3 is a human breast cancer cell-line with highlevels of FASN expression. It is estimated that FASN comprises about 25%of the cytosolic proteins in this cell line. SKBr3 cells werehomogenized in a dounce homogenizer then centrifuged for 15 minutes at4° C. to remove particulate matter. The supernatant was then analyzedfor protein content, diluted to the appropriate concentration, and usedto measure FASN activity. The presence of FASN was confirmed by westernblot analysis. A similar method for isolation of FASN from SKBr3 cellsis described in Teresa, P. et al. (Clin. Cancer Res. 2009; 15(24),7608-7615).

FASN activity of the SKBr3 cell extract was determined by measuringeither NADPH oxidation or the amount of thiol-containing coenzyme A(CoA) released during the fatty acid synthase reaction. The dye CPM(7-diethylamino-3-(4′-maleimidyl-phenyl)-4-methylcoumarin) contains athiol reactive group that increases its fluorescence emission onreaction with the sulfhydryl group of CoA. The biochemical activitiesshown in Table 1 were determined using the fluorescence measurement ofCoA release via a procedure described in Chung C. C. et al. (Assay andDrug Development Technologies, 2008, 6(3), 361-374).

Example 2 Antiviral Activity

The antiviral activity of Structure (I-Z) was assessed using the HCV1breplicon system:

The replicon was constructed using the ET (luc-ubi-neo/ET) cell line, aHuh7 human hepatoma cell line harboring an HCV replicon with a stableluciferase (Luc) reporter and three cell culture-adaptive mutations(Pietschmann, et al (2002) J. Virol. 76:4008-4021). The HCV repliconantiviral evaluation assay examined the effects of compounds at sixhalf-log concentrations. Human interferon alpha-2b was included in eachrun as a positive control compound. Sub-confluent cultures of the ETline were plated out into 96-well plates that are dedicated for theanalysis of cell numbers (cytotoxicity) or antiviral activity and thenext day drugs were added to the appropriate wells. Cells were processed72 hr later when the cells were still sub-confluent. EC₅₀(concentrations inhibiting the replicon by 50% and 90%, respectively),IC₅₀ (concentration decreasing cell viability by 50%) and SI (selectiveindex: IC₅₀/EC₅₀) values were determined. HCV RNA replicon levels wereassessed as either HCV RNA replicon-derived. Luc activity or as HCV RNAby TaqMan RT-PCR. Two methods were used to estimate cell counts(cytotoxicity). When the Luc assay system was employed, the colorimetricCytoTox-1 cell proliferation assay (Promega) was used to estimate cellnumbers, while ribosomal RNA (rRNA) levels determined via TaqMan RT-PCRwere used as an indication of cell numbers in the RNA-based assay. Asummary of the results is listed below in Table 2.

TABLE 2 Replicon EC50 Cell IC50 Selectivity Method (μM) (μM) IndexLuciferase activity 0.017 >32 >1882 TaqMan RT-PCR 0.105 >100 >952

Example 3 FASN Inhibition Correlates to HCV Inhibition

The antiviral activities of 15 compounds of the present disclosure(numbers correlate to the compounds in Table 1) were measured using theHCV replicon system. Replicon cell line 1b (HCV 1b/Luc-Neo replicon (1bCon1 with Firefly gene integrated)) was established following publishedmethods (Lohmann et al. (1999) Science 285(5424):110-113, Lohmann et al.(2001) J. Virol. 75(3):1437-1449 and Qi et al. (2009) Antiviral Res.81(2):166-173) using Huh7 by G418 selection. The replicon was assembledusing synthetic gene fragments. The GT1b line has PV-EKT and harbors 3adaptive mutations E1202G(NS3), T1280I(NS3), K1846T(NS4B) and thebackbone is Con1. The culture medium was:

DMEM supplement with 10% FBS, G418 (250 μg/ml), streptomycin (100μg/ml)/penicillin (100 U/ml) , L-glutamine (100×), NEAA (100×)

Media prepared as follows:

500 ml DMEM media (Gibco, Cat #11960-077)

57 ml Fetal Bovine Serum (Gibco, Cat #16140-071)

5.7 ml Penicillin-Streptomycin (Gibco, Cat #15140-122)

5.7 ml MEM non-essential amino acids (Gibco, Cat #111140-050)

5.7 ml L-glutamine (Gibco, Cat #125030-081)

574.1 ml media+2.87 ml 50 mg/ml G418 [final 0.25 mg/ml] (Gibco, Cat#10131-027)

Compounds were dissolved in DMSO to provide a 10 mM stock or used fromstock DMSO solutions. Compounds were diluted to generate 10-point halflog (3.16-fold) serial dilutions for assay in 384-well plates (Echoqualified 384-well PP (Labcyte Cat #P-05525)) plus DMSO in duplicate.This experiment was repeated three times on three different days.

Cells were harvested when confluency reached 90%-100%. Cellconcentrations were adjusted to 8×10⁴ cells/ml and added to 384-wellwhite assay microplates (tissue-culture treated—Greiner Cat #781080) toreach a final cell density of 2,000 cells/well. Plates were incubated at5% CO₂ and 37° C. for 72 hours.

After 72 hours of incubation Bright-Glo Luciferase reagent (Promega, cat#E2650) and Cell Titer Flo (Promega, cat #G6080/1/2) were prepared andstored in the dark while equilibrating to room temperature. Treatedcells were likewise equilibrated to room temperature. 10 μL of CellTiter Flo was added to each well of compound-treated cells and incubatedin microtiter plates for approx. 0.5 hours. Cell viability was measuredusing an Envision reader (available from Perkin Elmer) to estimatecytotoxicity. 30 μL of firefly luciferase substrate were added to eachwell and chemiluminescence was measured as an indicator of the extent ofHCV replication.

The anti-replicon activity (% inhibition) is calculated using theequation:

${\% \mspace{14mu} {Inhibition}} = {\left( {1 - \frac{{Cmpd} - {Control}}{{DMSO} - {Control}}} \right) \times 100.}$

Cytotoxicity is calculated using the equation:

${\% \mspace{14mu} {Cytotoxicity}} = {\left( {1 - \frac{{Cmpd} - {Background}}{{DMSO} - {Background}}} \right) \times 100.}$

There was determined to be a correlation between potency of FASNinhibition and antiviral activity as illustrated in Table 3 below andFIG. 1. It is noted that none of the compounds caused significantcytotoxicity.

TABLE 3 Biochemical IC50 Antiviral EC50 Molecule (μM) (μM) 1 0.230 0.4252 0.065 0.192 12 0.370 1.003 14 0.263 0.260 20 0.022 0.011 27 0.1070.153 43 0.110 0.154 55 0.035 0.034 58 0.025 0.078 67 0.090 0.270 680.100 0.301 70 0.037 0.099 73 0.040 0.117 152 0.052 0.072 343 0.6000.624

Example 4 FASN Inhibitors Retain Activity Against HCV Mutants thatConfer Resistance to Direct-Acting Antiviral Agents

One of the major challenges in treating hepatitis C is the rapidemergence of resistance in response to direct-acting antiviral agents.Resistance typically results when the virus generates a point mutantthat supports essential viral functions but prevents antiviral agentsfrom binding. Three FASN inhibitors (compounds 55, 20, and 70) weretested for their ability to inhibit mutants of HCV that conferresistance to representative antiviral agents. Each of these mutants wasintroduced into a GT1b construct based on a Con1 backbone containing thePVIRES-Luciferase Ubi-Neo gene and harboring 1 adaptive mutation(S22041). (Lohmann et al. (1999) Science 285(5424):110-113, Lohmann etal. (2001) J. Virol. 75(3):1437-1449 and Qi et al. (2009) Antiviral Res.81(2):166-173). Antiviral activities were measured by the methoddescribed in Example 3.

The studied mutations are shown in Table 4 below.

TABLE 4 Studied Mutations Mutant Reference NS3 A156T Susser et al J.Clin. Virol.52(4), 321-327 (2011) and references therein NS3 R155KSusser et al J. Clin. Virol.52(4), 321-327 (2011) and references thereinNS4B H94R Rai et al. Antiviral Res. 90, 93-101 (2011) NS5AY393H Fridellet a.l Antimicrob. Agents Chemother. 54(9), 3641-3650 (2010) NS5B M423I(non-nucleoside site) Troke et al. Antimicrob. Agents Chemother. 56(3),1331-1341 (2012) NS5B S282T (nucleoside site) Dutartre et al.Antimicrob. Agents Chemother.50(12), 4161-4169 (2006)

A known NS4B allosteric inhibitor (Compound A), a known NS5A inhibitor(Compound B), a known non-nucleoside NS5B inhibitor (Compound C), aknown NS3/NS4A protease inhibitor (Compound. D) and a known nucleosideNS5B inhibitor (Compound E) were tested in parallel with the FASNinhibitors of the present disclosure to confirm the performance of theresistance mutations.

Antiviral EC₅₀'s for the various compounds against the panel of mutants,along with the relative shift in EC₅₀ relative to the GT1b wild-typereplicon are shown below. Normal assay variation is ±3-4 fold. EC₅₀shifts outside this range imply resistance and are indicated in bold.The 3 FASN inhibitors retain activity across the panel of mutants,whereas the direct-acting antiviral agents display resistance againstmutations in their respective binding sites.

TABLE 5 Antiviral EC₅₀s. EC₅₀ (nM) 1b Wild NS3 NS3 NS4B NS5A NS5B NS5BCompound Type A156T R155K H94R Y93H M423I S282T 55 49.63 143.00 156.1067.31 109.40 19.22 73.30 20 16.71 44.06 25.46 17.02 32.00 19.70 25.60 7039.18 49.97 43.91 36.00 108.90 58.69 56.90 Compound A 261.00 232.20209.60 2813.00 n.t. 126.60 n.t. Compound B 0.01 0.01 n.t. n.t. 0.28 0.010.01 Compound D 0.67 105.00 236.60 0.39 n.t. 1.54 n.t. Compound C 4.274.57 8.43 4.61 3.00 34.09 3.00 Compound E 583.70 890.90 n.t. n.t. 1069.0159.30 15650.0

TABLE 6 Fold shift in EC50 relative to wild-type HCV Fold shift in EC50relative to wild-type Binding NS3 NS3 NS4B NS5A NS5B NS5B Compound SiteA156T R155K H94R Y93H M423I S282T 55 2.88 3.15 1.36 2.20 0.39 1.48 202.64 1.52 1.02 1.92 1.18 1.53 70 1.28 1.12 0.92 2.78 1.50 1.45 CompoundA NS4B 0.89 0.80 10.78 n.t. 0.49 n.t. Compound B NS5A 1.00 n.t. n.t.35.13 0.75 0.88 Compound D NS3/4A 156.46 352.56 0.58 n.t. 2.29 n.t.Compound C NS5B 1.07 1.98 1.08 0.70 7.99 0.70 (non-nuc) Compound E NS5B1.53 n.t. n.t. 1.83 0.27 26.81 (nuc)

Example 5 FASN Inhibitors Useful in Combination Therapies

This example describes the in vitro antiviral activity and cytotoxicityof the compound of Structure (V-K) in combination with IFN-α, Ribavirin,Compounds B, C, D and E against an HCV replicon cell line.

Materials:

Virus: The GT1b replicon plasmid was assembled using synthetic genefragments. The replicon genome contains PVIRES-Luciferase Ubi-Neo genesegments and harbors 1 adaptive mutation (S22041), and the backbone isCon1. The replicon GT1b cell line was established by the followingpublished methods.

Medium and Reagents: Table 7 below provides details regarding theculture medium reagents used in this example.

TABLE 7 List of culture medium regents Reagent Vendor Catalogue NumberDimethyl sulfoxide (DMSO) Sigma Cat #34869-100ML DMEM Invitrogen Cat#11960-044 Fetal Bovine Serum (FBS) Gibco Cat #16140 Pen-StrepInvitrogen Cat #15140-122 MEM non-essential amino acids Invitrogen Cat#11140-050 L-Glutamin Invitrogen Cat #25030-081 G418 (geneticin) GibcoCat #10131-027 Trypsin/EDTA Invitrogen Cat #25200-072 DPBS/ModifiedHyclone SH30028.01B 96-well cell plate Greiner Cat #655090 Cell titerfluoro Promega Cat #G6082 Bright-Glo Promega Cat #E264B

Analytical Instruments: The following analytical instruments were usedto perform the assays of this example:

-   POD-810-   Topcount (PE)-   Envision (PE)-   Multidrop (Thermo)

Methods:

Preparation of compound plates for single compound testing: Compoundswere supplied as dry powders and were reconstituted in DMSO to generatestock solutions. The POD-810 system was used to generate 10-point halflog (3.16-fold) serial dilutions for the assay in 96-well plates. Thehighest test concentrations are detailed for each compound in Table 8.

Assay Protocol (single compounds): Each compound was assayed with3.16-fold (half log) serial dilutions for 10 concentrations plus DMSO induplicate. HCV replicon GT1b cells were harvested and adjusted to a cellconcentration of 8E±04 cells/ml. A Multidrop was used to plate 100μL/well into 96 assay microplates to reach a final cell density of 8,000cells/well. Plates were incubated at 5% CO₂, 37° C. for 72 hours.

At the end of the 72 hour incubation, antiviral activity andcytotoxicity were measured. Bright-Glo Luciferase reagent and Cell TiterFlo were prepared and stored in dark while equilibrating to roomtemperature. The cell plates were allowed to equilibrate to roomtemperature as well. A Multidrop was used to add 20 μL Cell Titer Flo toeach well of compound-treated and compound-free cells. The plates areincubated for 1 hour, and cell viability is measured on an Envisionreader for cytoxicity calculation. Fifty microliters of fireflyluciferase substrate are added to each well, incubated for 2 minutes,and chemiluminescence is measured for EC₅₀ calculation.

The anti-replicon activity (% inhibition) was calculated using thefollowing equation:

% Inhibition=[1−((Compound-background)/(DMSO-background))×100].

Test compounds and assay setup for two-compound combination studies: TheDMSO stocks of the compounds used in the single compound testing werealso used in this analysis. Combination dilution matrixes were generatedby POD-810 in 96-well assay microplates. The POD-810 system was used togenerate 7-point, 2-fold serial dilutions in a matrix format. Themaximum concentration tested for each compound is detailed below.

TABLE 8 Expected activities and upper concentrations of compounds testedin single-agent and combination studies Highest Highest concentrationconcentration Expected for single-agent for combination GT1b EC50testing testing Compound (μM) (μM) (μM) (V-K) 0.060 10.0 0.100 CompoundD 0.0014 0.032 0.0032 Compound C 0.018 10.0 0.032 Compound B 0.0000090.001 0.000032 Compound E 4.030 100.0 10.0 IFN 64.94 IU/ml 1000 IU/ml10.0 IU/ml Ribavirin 26.830 320.0 100.0

The compound of Structure (V-K) was tested atone and in combination withcompounds detailed in Table 9. Each compound was also tested alone as asingle agent.

TABLE 9 Combinations of compounds for in vitro evaluation. RegimenCombination 1 (V-K) + Compound D 2 (V-K) + Compound C 3 (V-K) + CompoundB 5 (V-K) + Compound E 6 (V-K) + IFN-α 7 (V-K) + RBV

Assay Setup (two-drug combinations): Each compound was assayed with2-fold serial dilutions for 7 concentrations in matrix format plus eachdrug alone. HCV replicon GT1b cells were harvested and adjusted to acell concentration of 8E±04 cells/ml. A Multidrop was used to plate 100μL into 96 assay microplates to reach a final cell density of 8,000cells/well. Plates were incubated at 5% CO₂, 37° C. for 72 hours.

At the end of the 72 hour incubation, antiviral activity andcytotoxicity were measured. Bright-Glo Luciferase reagent and Cell TiterFlo were prepared and store in dark while allowing to equilibrate toroom temperature. The cells plates were allowed to equilibrate to roomtemperature as well. A Multidrop was used to add 20 μL Cell Titer Flo toeach well of compound-treated and compound-free cells. The plates wereincubated for 1 hour, and cell viability was measured on an Envisionreader for cytotoxicity calculation. The liquid was then removed fromthe plates, after which 50 μL PBS and 50 μL firefly luciferase substratesolution were added to each well, after a 2-minute incubation period,chemiluminescence (for HCV replication calculation) was measured. Thedata were analyzed using MacSynergy™ II.

Assay Results:

Activity and cytotoxicity of the compounds. The EC₅₀ and CC₅₀ values aresummarized below in Table 10.

TABLE 10 EC₅₀ and CC₅₀ of Each Test Compound GT1b Expected EC₅₀ CompoundEC₅₀ (μM) (μM) CC₅₀ (μM) (V-K) 0.04 0.06 >10 Compound D 0.00210.0014 >0.032 Compound C 0.006 0.018 >10 Compound B 0.0000120.000009 >0.001 Compound E 2.41 4.03 >100 IFN-α (IU/mL) 1.34 1 >1000 RBV32.75 26.83 239

Combination Effect. The combination effect of the compound pairs wascalculated using MacSynergy™ II and those results are summarized inTable 11 below.

TABLE 11 Summary of the combination effects of the compound pairsMacSynergy ™ II Compd 1 Compd 2 (top SYNERGY PLOT (95%) (top conc) conc)SYNERGY Log volume ANTAGONISM Log volume (V-K) Compound D 16.7 1.51−13.03 −1.18 Compound C 2.93 0.27 −9.2 −0.83 Compound B 6.75 0.61 −7.11−0.64 Compound E 1.08 0.1 −7.81 −0.73 IFN-α 5.44 0.49 −24.88 −2.25 RBV1.64 0.15 −3.52 −0.32 * None of the combinations cause cytotoxicity.

Conclusions

The Z factors of the compound pairs summarized in Table 12 indicate thatthe assay quality is better than the QC standard.

TABLE 12 Summary of the Z factor of compound pairs Z factor Drug PairsPlate-1 Plate-2 Plate-3 (V-K) + Compound D 0.68 0.86 0.83 (V-K) +Compound C 0.66 0.78 0.65 (V-K) + Compound B 0.70 0.83 0.84 (V-K) +Compound E 0.72 0.76 0.74 (V-K) + IFN-α 0.75 0.70 0.66 (V-K) + RBV 0.780.78 0.72

The EC₅₀ values of the individual compounds in the combination matrix(summarized in Table 13) are consistent with the EC₅₀ data in obtainedfor single-compound inhibition Table 10.

TABLE 13 Summary of EC₅₀ of single dose in compound combination GT1bEC₅₀ (μM) in dose ranging EC₅₀ (μM) of single dose Compound assay indrug combination (V-K) 0.04 0.07 Compound D 0.0021 0.0017 Compound C0.006 0.009 Compound B 0.000012 0.000009 Compound E 2.41 1.79IFN-α(IU/mL) 1.34 3.43 RBV 32.75 31.63

The compound of Structure (V-K) was demonstrated to have additiveantiviral activity without enhanced cytotoxicity in combination withagents representing a variety of mechanisms. These results aresummarized in Table 14 below.

TABLE 14 Summary of antiviral mechanisms that are additive with thecompound of Structure (V-K). The term “direct-acting antiviral” (“DAA”)refers to a compound that binds to and inhibits a viral protein, ratherthan a host protein. Molecule Mechanism Class IFN-α Cellular defenseHost RBV Multiple Host Compound D HCV Protease DAA Compound B NS5AInhibitor DAA Compound C NS5B Inhibitor DAA Compound E NS5B InhibitorDAA

IFN-α and RBV represent current standard-of-care for treating HepatitisC infection, and the HCV protease inhibitors Telaprevir and Boceprivirhave recently been approved. The additive antiviral activity and lack ofenhanced cytotoxicity in combination with IFN-α and RBV further suggestthat compounds of this invention will not interfere with critical hostprocesses such as cellular defense (IFN-α) or guanidine nucleotidebiosynthesis (RBV). Compounds of this invention such as the compound ofStructure (V-K) should therefore be therapeutically useful ifadministered in combination regimens with current standard of care.Moreover, the additive antiviral activities observed with Compound B,Compound C, and Compound E suggest that molecules of this invention suchas the compound of Structure (V-K) can be productively combined withagents currently in development that target newer mechanisms (e.g., NS5Aand NS5B inhibitors).

Example 6 Anti-Tumor Activity—Multiplexed Cytotoxicity Assay

Cells were grown in RPMI1640, 10% FBS, 2 mM L-alanyl-L-Glutamine, 1 mMNa pyruvate or a special medium in a humidified atmosphere of 5% CO₂ at37° C. Cells were seeded into 384-well plates and incubated in ahumidified atmosphere of 5% CO₂ at 37° C. Compounds were added 24 hourspost cell seeding. At the same time, a time zero untreated cell platewas generated.

After a 72 hour incubation period, cells were fixed and stained withfluorescently labeled antibodies and nuclear dye to allow visualizationof nuclei, apoptotic cells and mitotic cells. Apoptotic cells weredetected using an anti-active caspase-3 antibody. Mitotic cells weredetected using an anti phospho-histone-3 antibody.

Compounds were serially diluted in half-log (3.16-fold) increments andassayed over 10 concentrations in a final assay concentration of 0.1%DMSO from the highest test concentration specified in the sampleinformation chapter. Automated fluorescence microscopy was carried outusing a GE Healthcare IN Cell Analyzer 1000, and images were collectedwith a 4× objective.

Twelve bit tiff images were acquired using the InCell Analyzer 1000 3.2and analyzed with Developer Toolbox 1.6 software. EC₅₀ and IC₅₀ valueswere calculated using nonlinear regression to fit data to a sigmoidal 4point, 4 parameter One-Site dose response model, where: y(fit)=A+[(B−A)/(1+((C/x){circumflex over ( )}D))]. Curve-fitting,EC₅₀/IC₅₀ calculations and report generation are performed using acustom data reduction engine MathIQ based software (AIM).

The multiplexed cytotoxicity assay uses a cell image based analysistechnique where cells are fixed and stained with fluorescently labeledantibodies and nuclear dye to visualize nuclei, and apoptotic andmitotic cells. Apoptotic cells are detected using an anti-activecaspase-3 antibody. Mitotic cells are detected using an antiphospho-histone-3 antibody.

Cell proliferation is measured by the signal intensity of theincorporated nuclear dye. The cell proliferation assay output isreferred to as the relative cell count. To determine the cellproliferation end point, the cell proliferation data output istransformed to percent of control (POC) using the following formula:

POC=relative cell count (compound wells)/relative cell count (vehiclewells)×100

Time zero non-treated plate is used to determine number of doublings in72 hour assay period: Number of doublings in 72 hours=LN[Cell number (72hr end point)*Cell number (time zero)]/LN(2). The output of eachbiomarker is fold increase over vehicle background normalized to therelative cell count in each well.

The activated caspase-3 marker labels cells from early to late stageapoptosis. The output is shown as a fold increase of apoptotic cellsover vehicle background normalized to the relative cell count in eachwell. Concentrations of test compound that cause a 5-fold induction inthe caspase-3 signal indicates significant apoptosis induction. Wellswith concentrations higher than the relative cell count IC₉₅ areeliminated from the caspase3 induction analysis.

The phospho-histone-3 marker labels mitotic cells. The output is shownas a fold induction of mitotic cells over vehicle background normalizedto the relative cell count in each well. When the fold induction ofmitotic cell signal over background is ˜1, there is “no effect” on thecell cycle. Two or more fold increase in phospho-histone-3 signal overvehicle background indicates significant test compound induction ofmitotic block.

Two or more fold decrease in the phospho-histone-3 signal may indicateG-1/S block only when cytotoxicity levels are below the measuredrelative cell count IC₉₅. When 2 or more fold decrease in thephospho-histone-3 signal are observed at concentrations higher than therelative cell count IC₉₅, the decrease in mitotic cell counts are mostlikely due to a more general cytotoxicity effect rather than a trueG-1/S phase block. Wells with concentrations higher than the relativecell count IC₉₅ are eliminated from the phospho-histone-3 analysis.

Cell proliferation measured by relative cell counts were the criteriafor positive response.

Apoptosis:

>5-fold increase in activated caspase-3 signal indicates an apoptoticresponse.

Mitosis:

>2-fold increase in phospho-histone-3 indicates mitotic block.

<2-fold decrease in phospho-histone-3 indicates G1/S block.

TABLE 15 Results Max G1/S cell Max G2/M Apoptosis Biochemical cycleblock cell cycle Fold Compound IC₅₀ (μM) (μM) block Induction 205 0.2200.160 1.36 2.39 95 0.030 0.012 0.94 2.45 142 0.140 0.031 1.28 2.34 1530.060 0.014 1.17 2.55 427 0.080 0.019 1.00 2.39 42 0.070 0.013 1.09 2.2048 0.170 0.027 1.27 2.20 156 0.030 0.031 1.28 2.59 182 0.150 0.030 1.542.07 183 0.170 0.031 1.00 2.40

Example 7 Effects of FASN Inhibitors on Fatty Liver disease in Mice

The impact a FASN inhibitor of the present application on steatosis wasdetermined in C57BL/6 male mice on a high fat diet (HFD).

This example describes the effects of Compound 364A.

2 groups of 5 male C57BL/6NCrSim mice were employed vehicle and FASNinhibitor treated groups, which were 4-5 weeks old at the start ofdosing. Mice were allowed unrestricted access to a diet high in fat(Research Diets cat. No. D09100301: 40% kcal partially hydrogenatedvegetable oil shortening and by weight 20% fructose and 2% cholesterol).In addition, all animals received once-daily oral doses of vehicle or 10mg per kg of mouse body weight of a FASN inhibitor of the applicationfor 57 consecutive days. At sacrifice, the right liver lobe was placedin a preservative (10% neutral buffered formalin) followed bypreparation of liver samples for microscopic evaluation by a licensedpathologist. Liver samples were either stained for fat using Oil Red Ostain or collagen with Masson's trichrome stain.

Slides were prepared from right liver lobes and stained with Oil Red Ofor fat and Masson's Trichrome for collagen. For study 1, thehistopathologic findings for Oil Red O and Trichrome stains aresummarized in Table 16 and representative images for stains are shown inFIG. 2. Animals receiving vehicle for 57 days while on a HFD developedsevere fat deposits inside the liver cells. The liver cells wereenlarged and filled with small vesicles of lipid as indicated by the OilRed O staining. There was no significant inflammation or accumulation ofcollagen. Animals on RFD which received Compound 364A at 10 mg/kg for 57days had no evidence of fat deposits inside the liver cells and appearednormal. These results are illustrated by the representative images inFIG. 2, where lipid deposition and liver cell enlargement present in thevehicle controls are totally absent in the normal-appearing livers fromanimals treated with Compound 364A at 10 mg/kg. These resultsdemonstrate that prophylactic, once daily dosing of 10 mg/kg Compound364A inhibited the development of steatosis in this model. These resultssupport the utility of FASN inhibitors in the treatment of NAFLD, NASHand metabolic syndrome.

TABLE 16 Study 1 histopathologic evaluation of stained sections of liverand ranked hepatic steatosis severity Oil Red O for Trichrome forGeneral Test Article Animal Intracellular Lipid Histology and FibrosisVehicle 1 4 4 Vehicle 2 4 4 Vehicle 3 3 4 Vehicle 4 3 4 Vehicle 5 3 4Compound 364A @ 6 0 0 10 mg/kg Compound 364A @ 7 0 0 10 mg/kg Compound364A @ 8 0 0 10 mg/kg Compound 364A @ 9 0 0 10 mg/kg Compound 364A @ 100 0 10 mg/kg

A second study employed 3 groups of 5 male C57BL/6J mice (vehicle for 28days, vehicle for 57 days and vehicle for 28 days followed by treatmentwith a FASN inhibitor compound of the application for 29 days) whichwere 4-5 weeks old at the start of dosing. Mice were allowedunrestricted access to a diet high in fat (Research Diets cat. No.D09100301: 40% kcal partially hydrogenated vegetable oil shortening andby weight 20% fructose and 2% cholesterol). At sacrifice, the rightliver lobe was placed in a preservative (10% neutral buffered formalin)followed by preparation of liver samples for microscopic evaluation by alicensed pathologist. Liver samples were either stained for fat usingOil Red O stain or collagen with Masson's trichrome stain.

The histopathologic findings for tissue staining are summarized in Table17 and representative H&E stained images for Study 2 are shown in FIG.3. Animals dosed with vehicle for 57 days while on a HFD developedsevere fat deposits inside the liver cells. Fewer and much smaller fatdeposits were observed in the livers from animals which were dosed withvehicle for 28 days followed by Compound 364A for 29 days even thoughthese animals had received the HFD for a total of 57 days. These resultsdemonstrate that therapeutic, once daily dosing of 10 mg/kg Compound364A inhibited progression of hepatic steatosis in this model.

TABLE 17 Study 2 histopathologic evaluation of stained sections of liverand ranked hepatic steatosis severity Overall Group Animal Hepaticchanges Histopathologic findings 1 1 moderate[3] Variable-sized vacuolesthroughout section Vehicle 28 2 moderate[3] Variable-sized vacuolesthroughout section Days 3 marked[4] Some enlargement/ballooning ofhepatocytes numerous variable-sized vacuoles 4 moderate[3]Variable-sized vacuoles throughout section with few large vacuoles 5moderate[3] Variable-sized vacuoles throughout section 6 minimal[1] Fewsmall vacuoles identified 7 moderate[3] Variable-sized vacuolesthroughout section with few large/ballooning hepatocytes 8 mild[2] Smallsingle and multiple vacuoles within hepatocytes 9 marked[4] Focus ofcellular alteration (fatty change) enlargement/ballooning of hepatocytesnumerous large vacuoles 10 marked[4] Numerous large vacuolesenlargement/ballooning of hepatocytes foci of necrosis 2 11 severe[5]Diffuse enlargement/ballooning of hepatocytes Vehicle cytoplasmicrarefaction, scattered large 57 Days vacuoles 12 severe[5] Diffuseenlargement/ballooning of hepatocytes cytoplasmic rarefaction, largevacuoles in subcapsular region 13 marked[4] Numerous variable-sizedvacuoles throughout section 14 marked[4] Some enlargement of hepatocytesnumerous variable-sized vacuoles throughout section 15 severe[5] Diffuseenlargement/ballooning of hepatocytes cytoplasmic rarefaction, largevacuoles in subcapsular region 16 severe[5] Diffuseenlargement/ballooning of hepatocytes cytoplasmic rarefaction, largevacuoles in subcapsular region 17 severe[5] Diffuseenlargement/ballooning of hepatocytes cytoplasmic rarefaction, fewvacuoles in subcapsular region 18 moderate[3] Variable-sized vacuolessome enlargement of hepatocytes 19 severe[5] Diffuseenlargement/ballooning of hepatocytes cytoplasmic rarefaction, largescattered vacuoles 20 marked[4] Some enlargement of hepatocytes fewvacuoles 3 21 marked[4] Multifocal enlargement/ballooning of Vehiclehepatocytes, occasional large vacuoles 28 Days; C 22 marked[4]Multifocal enlargement/ballooning of Compound hepatocytes; numerousvariable-sized vacuoles 364A 29 throughout section days 23 moderate[3]Numerous small vacuoles; some enlargement/ballooning of hepatocytes 24marked[4] Multifocal enlargement of hepatocytes numerous variable-sizedvacuoles throughout 25 marked[4] Numerous variable-sized vacuolesthroughout section 26 severe[5] Diffuse enlargement/ballooning ofhepatocytes cytoplasmic rarefaction; numerous small and large vacuoles27 marked[4] Multifocal enlargement/ballooning of hepatocytes; numerousvariable-sized vacuoles throughout section 28 moderate[3] Scatteredvariable-sized vacuoles 29 moderate[3] Scattered variable-sized vacuoles30 moderate[3] Scattered variable-sized vacuoles

Hepatic Steatosis Scoring System as described in Tables 1 and 2 above:0=Normal—Tissue considered to be normal under the conditions of thestudy and considering the age, sex and strain of the animal concernedAlterations may be present which, under other circumstances, would beconsidered deviations from normal. 1=Minimal—The amount of change barelyexceeds that which is considered to be within normal limits. 2=Mild—Ingeneral, the lesion is easily identified but of limited severity. Thelesion probably does not produce any functional impairment.3=Moderate—The lesion is prominent but there is significant potentialfor increased severity. Limited tissue or organ dysfunction is possible.4=Severe—The degree is either as complete as considered possible orgreat enough in intensity or extent to expect significant tissue ororgan dysfunction.

Example 8 Effects of FASN Inhibitors on IL-10 Levels In Vivo and InVitro

The impact of a FASN inhibitor of the present application on IL-1βlevels was evaluated in vivo and in vitro. This example describes theeffects of Compound 364A, Compound 6B and Compound 242A.

Fast-Fed Study in Rats

Female Sprague Dawley rats were fasted for 12 hours and then two groupswere dosed orally with a FASN inhibitor of the application at 60 mg/kgof body weight or 100 mg/kg. A separate control group was dosed with theformulation vehicle material. One hour later, the animals were allowedto feed for 6 hours followed by a 5 hour fast and then given anadditional 10 hours of feeding. Blood samples were collected at timepoints to determine the level of IL-1β.

High Fat Study in Mice

Two groups of male C57BL/6J mice were dosed orally once daily with aFASN inhibitor of the application at 3 mg/kg or 10 mg/kg. A separatecontrol group was dosed with the formulation vehicle material. Bloodsamples were collected at time points to determine the level of IL-1β.

Human IL-1b Study

Blood from healthy donors was treated with an anti-coagulant andperipheral blood mononuclear cells (PBMC) were isolated. The adherentmonocyte cells in the PBMC were selected by allowing cells to attach totissue culture dishes.

The FASN inhibitors of the application lowered the level of IL-1β betain blood serum which resulted after food intake in fasted rats or whichoccurred in mice fed a high fat diet. The release of IL-1β from freshlyisolated human blood cells was also reduced by treatment with a FASNinhibitor. These results support the utility of FASN inhibitors in thetreatment of inflammatory conditions that occur in NAFLD, NASH,metabolic syndrome and other inflammatory diseases.

In rats, which either were not treated or were given vehicle, IL-1βlevels in the serum progressively increased as a response to feedingafter fasting between 2 hour and 22 hours (FIG. 4). Treatment withCompound 6B prior to feeding reduced the IL-1 beta response over thiscomplete time course and by 22 hours the reduction was over 5 fold (FIG.5).

After 14 and 37 days on a high fat diet, the level of IL-1β wasdetermined in blood serum of the mice. Mice treated with Compound 364Ahad reduced levels of IL-1β beta at both 14 and 37 days, both beforereintroduction of food (FIGS. 6A and 6B) and after feeding (1 hr data inFIGS. 6A and 6B), compared to mice which received vehicle (FIGS. 6A and6B).

Human PBMC and monocytes in cell cultures were stimulated withlipopolysaccharide (LPS), a Toll 4 receptor agonist, or lipoteichoicacid (LTA), a Toll 2 receptor agonist. As shown in FIGS. 7A and 7B,without stimulation neither cell culture secreted IL-1 beta into thecell culture supernatants. Stimulation with either LPS or LTA plus DMSO,the solvent for Compound 242A, resulted in secretion of IL-1 beta.Compound 242A treatment of PBMC, which is a mixed population ofmononuclear cells including both lymphocytes and monocytes, reduced thelevel of IL-1 beta resulting from either LPS or LTA stimulation. Formonocytes, Compound 242A treatment reduced the level of IL-1 betaresulting from LTA stimulation whereas there was only a slight reductionafter LPS stimulation.

Example 9 Effects of FASN Inhibitors on T-Cell Differentiation

The impact of FASN inhibitors on the differentiation of naive CD4+ Tcells, isolated from mouse or human blood, into pro-inflammatory Th₁₇cells and anti-inflammatory T_(reg) cells was examined. This exampledescribes the effects of Compound 364A and Compound 152.

Naive T-Cell Isolation Procedure

Naive CD4+ T cells were isolated ex vivo from whole blood collected insodium citrate tubes and enriched with Dynabeads™ Untouched mouse (Cat#11415D) or human (Cat #11346D) CD4+ T Cells Isolation Kits (ThermoFisher). Naive mouse CD4+ T cells were plated into 48-well tissueculture plates (Costar) with 1 μg/mL anti-CD3 and anti-CD28 antibodycoated beads. Differentiation of naive mouse CD4+ T cells to generatemouse Th₁₇ cell cultures used medium containing the following additivesfor 4 days: anti-IL-2 (30 ng/mL) (R&D Systems); recombinant mouse IL-6(Peprotech) (10 ng/mL); recombinant human TGFbeta (1 ng/mL) (Peprotech);recombinant mouse IL-1 beta (10 ng/mL) (Peprotech); recombinant mouseIL-23 (10 ng/mL) (R&D Systems); anti-IL-4 antibody (20 ng/mL) (Biocell);and anti-IFNgamma antibody (50 ng/mL) (Biocell). Th₁₇ cells werecultured in IMDM GlutaMAX medium (Life Technologies) supplemented with10% heat-inactivated FCS (Biochrom), 500 U penicillin-streptomycin (LifeTechnologies).

Differentiation Procedure—Human T-Cells

Naive human CD4+ T cells were plated into 48-well tissue culture plates(Costar) with 1 μg/mL anti-CD3 with anti-CD28 antibody coated heads. SeeEndo et al., 2015, Cell Reports 12: 1042-1055. Differentiation of naivehuman CD4+ T cells to generate human Th₁₇ cultures used mediumcontaining the following additives for 4 days: anti-IL-2 (30 ng/mL) (R&DSystems); recombinant human IL-6 (10 ng/mL) (BD Biosciences);recombinant human TGFbeta (1 ng/mL) (BD Biosciences); recombinant humanIL-1beta (10 ng/mL) (BD Biosciences); recombinant human IL-23 (10 ng/mL)(BD Biosciences); anti-IL-4 antibody (20 ng/mL) (R&D Systems); andanti-IFNgamma antibody (50 ng/mL) (R&D Systems). Th₁₇ cells werecultured in IMDM GlutaMAX medium (Life Technologies) supplemented with10% heat-inactivated FCS (Biochrom), 500 U penicillin-streptomycin (LifeTechnologies).

Flow Cytometry

For mouse cells, monoclonal antibodies specific to the followingantigens (and labeled with the indicated fluorescent markers) were used:CD4 PerCP (GK1.5; 1:800), (Affymetrix/eBioscience); Foxp3 Alexa488(FJK-16s; 1:400), (Affymetrix/eBioscience); and IL-17A PE and IL-17A PE(eBio17B7; 1:400 and 1:200), (Affymetrix/eBioscience).

For human cells, monoclonal antibodies specific to the followingantigens (and labeled with the indicated fluorescent markers) were used:Foxp3 FITC (236A/E7, 1:100) (Affymetrix/eBioscience); IL-17A PE-Cy7(eBio64DEC17; 1:100) (Affymetrix/eBioscience); and CD4 PerCP (SK3;1:200) (BD Biosciences).

For analysis of surface markers, cells were stained in PBS containing0.25% BSA and 0.02% azide. Dead cells were excluded by LIVE/DEAD FixableDead Cell Stain Kit (Life Technologies).

For intracellular cytokine staining, cells were treated with Brefeldin A(5 mg/mL) for 2 h and stained using the Fixation/Permeabilization Kit(BD Biosciences) according to the manufacturer's instruction.

Quantitation of fluorescent cells and their intensity were acquired on aFACSCalibur (BD Biosciences), and data were analyzed with CELLQuestsoftware.

FASN inhibition (50 nM Compound 364A) of mouse CD4+ naive T cells with 4days of Th₁₇ differentiation conditions inhibits Th₁₇ celldifferentiation and stimulates T_(reg) differentiation. IL-17+ Th17cells fall from 41.2% of the CD4+ population to 3.9%, while FoxP3+ Tregcells increase from 0.04% to 23.8% of the CD4 + population with Compound364A treatment (FIGS. 8A and 8B).

FASN inhibition (50 nM Compound 364A) of human CD4+ naive T cells fromtwo different donors with 4 days of Th₁₇ differentiation conditionsinhibits Th₁₇ cell differentiation and stimulates T_(reg)differentiation. IL-17+ TH17 cells fall from 31% to 1.7% (donor 1) andfrom 37.2% to 1.6% (donor 2) of the CD4+ population, while FoxP3+ Tregcells increase from 0.05% to 24.2% (donor 1) and from 1.1% to 30.2%(donor 2) of the CD4+ population with Compound 364A treatment (FIGS.9A-9D).

FASN inhibition (100 nM Compound 152) of human CD4 + naive T cells fromtwo different donors with 4 days of Th17 differentiation conditionsinhibits TH₁₇ cell differentiation and stimulates Treg differentiation.IL-17+ TH17 cells fall from 30% to 10.3% (donor 1) and from 30.2% to6.4% (donor of the CD4+ population, while FoxP3+ Treg cells increasefrom 0.06% to 26.1% (donor 1) and from 0.04% to 20.4% (donor 2) of theCD4+ population with Compound 364A treatment (FIGS. 10A-10D).

The data clearly indicates that when naive CD4+ T cells are stimulatedto differentiate under pro-inflammatory conditions to generate Th₁₇inflammatory cells, FASN is required for this process and inhibition ofFASN with small molecule inhibitors such as Compound 364A or Compound152 prevents this pro-inflammatory differentiation and steersdifferentiation to the production of anti-inflammatory T_(reg) cellsinstead. These results support the utility of FASN inhibitors in thetreatment of inflammatory conditions that occur in NAFLD, NASH,metabolic syndrome and other inflammatory diseases.

While preferred aspects of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch aspects are provided by way of example only. Numerous variations,changes, and substitutions will now occur to those skilled in the artwithout departing from the invention. It should be understood thatvarious alternatives to the aspects of the invention described hereincan be employed in practicing the invention. It is intended that thefollowing claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

Example 10 Compound 364A Reverses Multiple Components of NASH in Mice

The ability of compound 364A to reverse the symptoms of establisheddiet-induced nonalcoholic steatoheptatitis in mice was investigated.

C57BL/6J mice were fed a high-fat/fructose/cholesterol diet (HFFCD) for44 weeks. For an additional eight weeks, animals continued ahigh-fat/fructose/cholesterol diet and received oral once-per-daytreatments of either Compound 364A, the anti-fibrotic pirfenidone, bothCompound 364A and pirfenidone, or vehicle control. At the end of thestudy, analyses included histological assessment (NAFLD Activity Score(NAS) and Fibrosis Stage), gene expression (liver) total triglycerideand cholesterol content (liver and plasma), levels of alaninetransaminase (ALT), and aspartate transaminase (AST) in plasma and serumcytokine levels.

Methods

Diet-induced animal models (DIO-NASH mouse model): The DIO-NASH mice arebased on male C57BL/6J mice fed a 60% high trans-fat diet with fructoseand cholesterol for 44 weeks prior to experiment. FIG. 11 shows aschematic of the study design and dose groups for FASN inhibitor 364Aand pirfenidone.

Liver biopsy: Mice were anesthetized with isoflurane (2-3%) inatmospheric air. A small abdominal incision was made in the midline andthe left lateral lobe of the liver was exposed. A cone shaped wedge ofliver tissue (approximately 50 mg) was excised from the distal portionof the lobe and fixated in 10% neutral buffered formalin (4%formaldehyde) for histology. The cut surface of the liver was instantlyelectrocoagulated using bipolar coagulation (ERBE VIO 100electrosurgical unit). The liver was returned to the abdominal cavity,the abdominal wall was sutured and the skin was closed with staplers.For post-operative recovery mice received carprofen (5 mg/kg)administered subcutaneously on OP day and post-OP day 1 and 2.

Blood sampling: During anesthesia with isoflurane, the abdominal cavitywas opened and cardiac blood was drawn with a regular syringe into EDTAtubes or with a coated (heparine/EDTA) vacutainer. Blood was placed at4° C.

Plasma preparation: Blood was centrifuged at 2000 g for 10 minutes. Theplasma supernatants were transferred to new tubes and immediately frozenin liquid nitrogen and stored at −80° C.

Blood and plasma assays (triglycerides (TG), total-cholesterol (TC),alanine transaminase (ALT), aspartate transaminase (AST)): Blood sampleswere collected in heparinized tubes and plasma was separated and storedat −80° C. until analysis. TG, TC, ALT, AST were measured usingcommercial kits (Roche Diagnostics, Germany) on the Cobas™ C-501autoanalyzer according to the manufacturer's instructions.

NAFLD activity score (NAS) and fibrosis stage: Liver samples were fixedin formalin, paraffin embedded, and sections were stained withhematoxylin and eosin (H&E) and Sirius Red. Samples were scored for NASand fibrosis stage (outlined below) using of the clinical criteriaoutlined by Kleiner et al. 2005. Total NAS score represented the sum ofscores for steatosis, inflammation, and ballooning, and ranges from 0-8.

TABLE 18 NAS and Fibrosis Stage Evaluation Guidelines Steatosis  <5% 0   5-33% 1 >33-66% 2 >66% 3 Lobular inflammation No foci 0 <2 foci/200x1 2-4 foci/200x 2 >4 foci/200x 3 Ballooning degeneration None 0 Few 1Many cells/prominent 2 ballooning Fibrosis None 0 Perisinusoidal orperiportal 1 Perisinusoidal & 2 portal/periportal Bridging fibrosis 3Cirrhosis 4

Liver tissue assays: Hydroxyproline is a major component of collagen andthe total content of collagen in liver was determined by colorimetricdetection of hydroxyproline using a QZBhypro, Quickzyme hydroxyprolineassay. Homogenized liver tissue was hydrolyzed by hydrochloric acid andthe supernatant transferred to a 96 well plate. The oxidizedhydroxyproline was reacted with 4-(Dimethylamino) benzaldehyde (DMAB),which resulted in a colorimetric product proportional to thehydroxyproline present. Absorbance was measured at 560 nm.

The triglyceride content in liver was determined using the Triglyceridereagent (Cat. no. 22-045-795, Roche Diagnostics, Germany) on the Cobas™C-111 autoanalyzer. Homogenized liver tissue was heated to 80-100° C.twice, centrifuged in a microcentrifuge and the triglyceride content wasmeasured in the supernatant.

The cholesterol content in liver was determined using the Cholesterolreagent (Cat. no. 22-045-780, Roche Diagnostics, Germany) on the Cobas™C-111 antoanalyzer. Homogenized liver tissue was heated to 80-100° C.twice, centrifuged in a microcentrifuge and the cholesterol content wasmeasured in the supernatant.

Histological staining procedures: In brief, slides with paraffinembedded sections were de-paraffinated in xylene and rehydrated inseries of graded ethanol.

Hentataxylin & Eosin (H&E) staining: The slides were incubated inMayer's Hematoxylin (Dako), washed in tap water, stained in Eosin Ysolution (Sigma-Aldrich), hydrated, mounted with Pertex and then allowedto dry before scanning.

Sirius red staining: The slides were incubated in Weigert's ironhematoxylin (Sigma-Aldrich), washed in tap water, stained inPicro-sirius red (Sigma-Aldrich) and washed twice in acidified water.Excess water was removed by shaking the slides and the slides were thenhydrated in three changes of 100% ethanol, cleared in xylene and mountedwith Pertex and allowed to dry before scanning.

Type I collagen IHC staining: Type I collagen (Southern Biotech, Cat.1310-01) IHC was performed using standard procedures. Briefly, afterantigen retrieval and blocking of endogenous peroxidase activity, slideswere incubated with primary antibody. The primary antibody was detectedusing a polymeric HRP-linker antibody conjugate. Next, the primaryantibody was visualized with DAB as chromogen. Finally, sections werecounterstained in hematoxyl in and cover-slipped.

Galectin-3 IHC staining: Galectin-3 (Biolegend, Cat. #125402) IHC wereperformed using standard procedures. Briefly, after antigen retrievaland blocking of endogenous peroxidase activity, slides were incubatedwith primary antibody. The primary antibody was detected using a linkersecondary antibody followed by amplification using a polymericHRP-linker antibody conjugate. Next, the primary antibody was visualizedwith DAB as chromogen. Finally, sections were counterstained inhematoxylin and cover-slipped.

IHC and steatosis quantification: MC-positive staining was quantified byimage analysis using the Visiomorph software (Visiopharm, Denmark).Visiomorph protocols are designed to analyse the virtual slides in twosteps. The first step is crude detection of the tissue at lowmagnification (1× objective). The liver capsule is excluded. The secondstep is detection of IHC-positive staining at high magnification (10×objective). The quantitative estimates of IHC-positive staing arecalculated as an area fraction (AF) according to Equation 1:

${AF}_{{IHC} - {{pos}.}} = \frac{{Area}_{{IHC} - {{pos}.}}}{{Area}_{fat} + {Area}_{tissue} + {Area}_{{IHC} - {{pos}.}}}$

Quantitiative assessment of steatosis: Steatosis was quantified on H&Estained slides by image analysis using the Visiomorph software(Visiopharm, Denmark). Visiomorph protocols analyse the virtual slidesin two steps. The first step is crude tissue detection at lowmagnification (1× objective). The second step is detection of steatosisat high magnification (20× objective). The quantitative estimates ofsteatosis are calculated as an area fraction according to Equation 2:

${AF}_{steatosis} = \frac{{Area}_{steatosis}}{{Area}_{tissue} + {Area}_{steatosis}}$

Results

In this diet-induced biopsy-confirmed mouse model of NASH, FASNinhibition with Compound 364A reduced hepatocyte ballooning, hepaticinflammation and steatosis, lowered plasma ALT and AST levels,diminished liver triglyceride and cholesterol and established asignature consistent with resolution of fibrosis including reducedexpression of collagens, alpha-SMA and TIMP1 and increased expression ofMMP9. Co-administration of pirfenidone further reduced liver fibrosiswhile maintaining the beneficial effects specific to FASN inhibition.

As shown in FIGS. 12-13, FASN inhibition by Compound 364A, alone or incombination with the anti-fibrotic pirfenidone improved liver function.FIG. 12 shows a liver function evaluation upon DIO-NASH mouse treatmentwith Compound 364A and pirfenidone by plasma liver biomarkers alanineaminotransferase (ALT) and aspartate aminotransferase (AST) and totalcholesterol (TC). FIG. 13 shows a liver function evaluation uponDIO-NASH mouse treatment with Compound 364A and pirfenidone by liversample biomarkers liver triglycerides and liver cholesterol.

As shown in FIGS. 14-18, FASN inhibition by Compound 364A reducedadverse liver symptoms alone or in combination with an antifibrotic. Thechanges in FIGS. 14-18 were scored as increased severity (I), no change(N) or decreased severity (D). FIG. 14 shows the change in liversteatosis upon DIO-NASH mouse treatment with Compound 364A andpirfenidone by liver biopsy analysis of histology. FIG. 15 shows thechange in liver inflammation upon DIO-NASH mouse treatment with Compound364A and pirfenidone by liver biopsy analysis of histology. FIG. 16shows the change in liver ballooning upon DIO-NASH mouse treatment withCompound 364A and pirfenidone by liver biopsy analysis of histology.FIG. 17 shows the change in liver fibrosis upon DIO-NASH mouse treatmentwith Compound 364A and pirfenidone by liver biopsy analysis ofhistology. FIG. 18 shows the change in liver overall health and NAFLDseverity, summarized by the NAFLD activity score (NAS) upon DIO-NASHmouse treatment with Compound 364A and pirfenidone by liver biopsyanalysis of histology.

As shown in FIGS. 19 and 20, FASN inhibition decreased the expression ofgenes responsible for causing fibrosis alone or in combination with anantifibrotic. FIG. 19 shows the change in liver collagen gene expressionupon DIO-NASH mouse treatment with Compound 364A and pirfenidone by geneanalysis of liver biopsies. FIG. 20 is a 2-D plot of the change incollagen gene expression upon DIO-NASH mouse treatment with Compound364A and pirfenidone by gene analysis of liver biopsies.

These results provide evidence in a diet-induced and biopsy-confirmedmouse model of NASH that FASN inhibition either alone or in combinationwith an anti-fibrotic agent can referse steatohepatitis.

Example 11 Compound 364A Reduces Collagen Accumumulation inBleomycin-Induced Murine Skin Fibrosis

The ability of Compound 364A to reduce collagen inflammation in in micewith bleomycin-induced skin fibrosis was investigated. Bleomycin-inducedskin fibrosis was established in C57/BL6 mice by daily subcutaneousinjection of bleomycin for 4 weeks. Oral once-per-day treatment withCompound 364A was concurrent with bleomycin injection or was begun after2 weeks of bleomycin injection. At the end of the study, collagencontent at the site of bleomycin injection was biochemically determined.FASN inhibition reduced skin collagen content whether treatment wasconcurrent with bleomycin injection or was begun after two weeks ofbleomycin injection.

Methods

Skin fibrosis protocol: Specific pathogen-free 6 weeks old femaleC57BL/6J mice were obtained. At Day 0, 50 mice were induced to developskin fibrosis by subcutaneous administration of bleomycin sulfate (BLM)in saline at a dose of 50 μg/mouse, with a volume of 50 μL every otherday (Day 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26). At Day0, 10 mice were induced to develop skin fibrosis by subcutaneousadministration of the BLM in saline at a dose or 50 μg/mouse with avolume of 50 μL every other day (Day 0, 2, 4, 6, 8, 10 and 12). Controlgroup mice were subcutaneously administered saline instead of the BLM.

FIG. 21 shows a schematic of the study design and dose groups for thestudy.

Randomization of the BLM-induced skin fibrosis model mice into 6 groupof 10 mice was based on the body weight on the day before the start oftreatment. Individual body weight was measured daily during theexperimental period. Survival clinical signs and behavior of mice weremonitored daily. If an animal showed >30% body weight loss compared toDay 0, and/or if it showed a moribundity sign such as prone position,the animal was euthanized ahead of study termination, and blood and skinsamples were collected according lo the protocol.

Groups: Group I (Control): Ten normal mice were kept without anytreatment until Day 28. Group 2 (Vehicle): Ten BLM-induced skin fibrosismodel mice were orally administered vehicle [30% PEG400 in water] in avolume of 5 mL/kg once daily from Day 0 to 28. Group 3 (Compound 364ALow): Ten BLM-induced skin fibrosis model mice were orally administeredvehicle supplemented with Compound 364A at a dose of 1 mg/kg once dailyfrom Day 0 to 28. Group 4 (Compound 364A Middle): Ten BLM-induced skinfibrosis model mice were orally administered vehicle supplemented withCompound 364A at a dose of 3 mg/kg once daily from Day 0 to 28. Group 5(Compound 364A High): Ten BLM-induced skin fibrosis model mice wereorally administrated vehicle supplemented with Compound 364A at a doseof 10 mg/kg once daily from Day 0 to 28. Group 6 (Compound 364ATherapeutic): Ten BLM-induced skin fibrosis model mice were orallyadministered vehicle in a volume of 5 mL/kg once daily from Day 0 to 13,and vehicle supplemented with Compound 364A at a dose of 10 mg/kg oncedaily from Day 14 to 28. Group 7 (Baseline): Ten BLM-induced skinfibrosis model mice were orally administered vehicle in a volume of 5ml/kg once daily from Day 0 to 14. Mice in Groups 1-6 were terminated 1hour after the last dose at Day 28, and mice in Group 7 were terminated1 hour after the last dose at Day 14 for the following assays.

Biochemical analysis: Skin collagen was quantified by a Sircol collagenassay kit.

Histological analysis of skin sections: For HE staining, sections werecut from paraffin blocks of skin tissue prefixed in 10% neutral bufferedformalin and stained with Lillie-Mayer's Hematoxylin and eosin solution.For quantitative analysis of dermal thickness, bright field images ofHE-stained sections were captured using a digital camera at 100-foldmagnification, and the dermal thickness in 5 fields/section weremeasured using ImageJ software (National Institute of Health, USA).

Sample Collection: For serum samples, blood was collected in serumseparate tubes without anticoagulant through direct cardiac puncture andthen centrifuged at 15,000×g for 2 minutes at 4° C. The supernatant wascollected and stored at −80° C. Skin samples were snap frozen in liquidnitrogen and stored at −80° C.

Statistical tests: Statistical tests were performed using the BonferroniMultiple Comparison Test. P values<0.05 were considered statisticallysignificant. A trend or tendency was assumed when a one-tailed t-testreturned P values<0.1. Results were expressed as mean±SD.

Results

In the bleomycin-induced skin fibrosis model, FASN inhibition withCompound 364A reduced skin collagen content in a dose-dependent mannerwhether treatment was concurrent with bleomycin injection or was begunafter two weeks of bleomycin injection: FIG. 22 shows a plot of thechange in skin collagen content by histological analysis of skinsections in the mice as a function of the dose of Compound 364A.

Example 12 Compound 364A Affects Gene Expression in Hepatic StellateCells

The relative mRNA expression of fibrotic genes in immortalized humanhepatic stellate cells (LX-2 cells) treated with Compound 364A orsorfenib was investigated.

Methods

Cell lines: Primary human hepatic stellate cells (phHSCs) andimmortalized human hepatic stellate cells (LX-2) were used.

Compound 364A and Sorafenib small molecules: Compound 364A was dissolvedin DMSO at 1, 3, 10 and 30 μM concentration stock solution followed by aseries of working concentrations of 5, 15, 50 and 150 nM in DMEM cellculture medium supplemented with 0.1% BSA without antibiotic. For thepositive control, the cells were treated in parallel with, a kinaseinhibitor, sorafenib at 7.5 μM concentration dissolved in DMSO.

Experimental Protocol: At the beginning of each experiment, stellatecells were serum-starved overnight in Dulbecco's Modified Eagle Medium(DMEM) supplied with 0.1% BSA (without antibiotic) to synchronizemetabolic activities of the cells. The cells were then exposed todifferent working concentrations of either Compound 364A or sorafenibfor 24, 48 and 72 hours.

Cell and gene analysis: Cell proliferation and cell apoptosis wereassessed by dye. Fibrogenic gene expression was assessed by real timePCR of (i) alpha smooth muscle actin; (ii) collagen I; (iii) beta PDGFreceptor; (iv) MMP2; (v) TIMP1; and (vi) TIMP2.

Cell cytotoxicity assay: 5,000 LX-2 cells or 10,000 phHSCs were platedper well in 96 well plates. Cells were starved overnight in DMEMsupplemented with 0.1% BSA (without antibiotic) to synchronize metabolicactivities of the cells. Cells were then incubated with differentconcentrations of Compound 364A for the indicated durations and MTSassays were accomplished using CellTiter 96 AQueous One Solution CellProliferation Assay kit according to manufacturer protocol.

Cell proliferation assay: 5,000 LX-2 cells or 10,000 phHSCs were platedper well in 96 well plates. After overnight serum starvation in DMEMsupplemented with 0.1% BSA (without antibiotic) the cells were exposedto Compound 364A at indicated concentrations. At 24 and 48 hours of drugexposure the cells were labeled with BrdU for either 2 hours (for LX-2cells) or 16 hours (for phHSCs) at 37 The cell proliferation ELISA, BrdUcolorimetric kit was used following the manufacturer's instructions.

Cell viability assay: 150,000 LX-2 cells or 200,000 phHSCs per well wereplated on 6-well plates. Cells were starved overnight in DMEMsupplemented with 0.1% BSA (without antibiotic) to synchronize metabolicactivities of the cells. Cells were then incubated with Compound 364A atthe indicated concentrations and durations. Cells were harvested andmixed (1:1) with 0.4% trypan blue stain. The viability of the cells wasimmediately counted in a Countess automated cell counter.

Fibrogenic gene expression in hepatic stellate cells by RT-qPCR: Thefollowing fibrogenic gene expressions were quantified by RT-qPCR: (1)Collagen1α1 (Col1α1); (2) Alpha Smooth Muscle Actin (αSMA); (3) BetaPDGF receptor (β-PDGFR); (4) Transforming growth factor-β receptor1(TGFβ-R₁); (5) Tissue inhibitor of metalloproteinase-1 (TIMP1); (6)Tissue inhibitor of metalloproteinase-2 (TIMP2); and (7) MatrixMetalloproteinase 2 (MMP2).

The kinase inhibitor Sorafenib (7.5 μM concentration) small molecule wasused as positive control and run in parallel. 150,000 LX-2 cells or200,000 phHSCs per well were plated on 6-well plates. Cells were starvedovernight in DMEM supplemented with 0.1% BSA (without antibiotic) tosynchronize metabolic activities of the cells. Cells were then incubatedwith either Compound 364A or sorafenib at the indicated concentrationsand durations. Cells were harvested and total RNA was extracted usingRNeasy Mini Kit. 0.5 μg of total RNA was used for reverse transcriptionwith an RNA to cDNA EcoDry Premix (Double Primed) Kit. Expression offibrogenic genes were measured by qPCR using custom designed primers andiQ SYBR Green Supermix on a LightCycler 480 II instrument.Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as ahousekeeping gene where the expression (Ct value) was constantthroughout different doses of Compound 364A as well as sorafenib.Fibrogenic genes were normalized to GAPDH.

Experimental data analysis: Each experiment was repeated at least threetimes. The data analysis was accomplished by using appropriatescientific and statistical software. Standard error (±SE) was calculatedaccording to student t-test. Unless otherwise specified, P valuessmaller than 0.05 were considered statistically significant.

Results

In vitro, FASN inhibition with Compound 364A dose-dependently reducedfibrogenic gene expression by real time PCR LX-2 liver cells. FIG. 23shows the relative mRNA expression of the fibrotic genes Col 1a1, αSMA,βPDGFR, TGFbR1, TIMP1, TIMP2, and MMP2 in immortalized human hepaticstellate cells (LX-2 cells) treated with Compound 364A or sorafenib for48 hours, followed by drug removal and rescue for 48 hours

The rescue of fibrogenic gene expression at 48 hours after withdrawal ofthe compound suggests the downregulation of the genes are not a toxiceffect of the compound.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Table 1 is given below:

ID Structure FASN IC₅₀ (μM) 1

0.230 2

0.065 2.9

0.060 3

0.146 4

0.200 5

0.055 6

0.360 7

0.050 8

0.125 9

0.040 11

0.170 12

0.370 13

0.260 14

0.263 15

0.180 16

0.058 17

0.073 18

0.990 19

0.870 20

0.022 21

0.045 22

0.085 23

0.070 24

0.070 25

0.150 26

7.195 27

0.107 28

0.490 29

0.980 30

0.320 31

0.060 32

0.215 33

7.500 34

0.080 35

25.083 36

0.130 37

0.675 38

2.345 39

1.710 40

0.050 41

0.035 42

0.067 43

0.110 44

0.180 45

0.147 46

0.050 47

0.230 48

0.170 49

0.040 50

0.520 51

1.700 52

31.650 53

1.970 54

0.310 55

0.035 56

2.800 57

0.030 58

0.025 60

0.045 61

0.230 62

0.093 63

0.510 64

0.170 65

0.090 66

0.230 67

0.090 68

0.100 69

0.065 70

0.037 71

0.030 72

0.200 73

0.040 74

0.120 75

0.130 76

0.035 77

0.080 78

0.035 79

0.045 80

0.400 81

0.200 82

0.077 83

0.090 84

5.320 85

1.450 86

5.420 87

0.310 88

0.040 89

0.030 90

0.380 91

2.210 92

0.940 93

0.550 94

5.260 95

0.030 96

0.030 97

0.025 98

0.900 99

0.220 100

>50 101

>50 102

0.085 103

0.035 104

0.130 105

0.015 106

0.900 107

1.490 108

1.050 109

0.250 110

0.280 111

0.135 112

1.295 113

0.130 114

0.245 115

0.480 116

0.090 117

0.090 118

0.350 119

120

0.460 121

2.300 122

0.890 123

0.690 124

32.880 125

>50 126

>50 127

0.730 128

2.260 129

>50 130

0.300 131

0.220 132

0.450 133

0.790 134

1.330 135

2.040 136

0.240 137

0.500 138

0.640 139

1.210 140

0.380 141

>50 142

0.140 143

0.175 144

0.320 145

0.820 146

0.260 147

0.250 148

0.180 149

0.240 150

0.300 151

0.420 152

0.052 153

0.055 154

0.105 155

0.20 156

0.030 157

0.090 158

0.057 159

0.070 160

0.055 161

0.040 162

0.115 163

0.135 164

>50 165

1.000 166

0.160 167

0.125 168

0.060 169

0.090 170

0.090 171

0.070 172

0.140 173

0.240 174

0.200 175

0.310 176

5.990 177

2.110 178

0.555 179

1.260 180

8.230 181

0.115 182

0.145 183

0.170 184

0.085 185

0.080 186

0.055 187

0.065 188

0.070 189

0.270 190

5.060 191

0.200 192

0.300 193

0.440 194

0.400 195

>50 196

>50 197

11.105 198

0.705 199

1.060 200

13.520 201

23.140 202

0.055 203

0.045 204

0.195 205

0.220 206

0.320 207

0.300 208

0.100 209

0.105 210

0.310 211

0.830 212

7.190 213

0.790 213

0.790 214

28.760 215

0.080 216

0.090 217

0.100 218

0.170 219

0.085 220

0.055 221

0.250 222

0.065 223

0.030 224

0.160 225

0.140 226

0.055 227

0.070 228

0.110 229

0.090 230

30.990 231

0.300 232

0.650 233

1.630 234

>50 235

0.030 236

0.060 237

0.080 238

0.100 239

0.050 240

0.050 241

0.120 242

0.050 243

0.120 244

0.220 245

0.020 246

0.050 247

0.020 248

0.060 249

0.070 250

0.030 251

0.580 252

0.180 253

0.090 254

0.090 255

0.410 256

0.090 257

0.580 258

0.150 259

1.330 260

3.500 261

21.750 262

5.343 263

0.250 264

>50 265

>50 266

>50 267

30.260 268

0.390 269

1.350 270

1.980 271

0.520 272

0.300 273

0.060 274

2.345 275

2.245 276

9.060 277

11.680 278

1.750 279

0.330 280

0.700 281

42.300 282

30.090 283

1.000 284

1.005 285

>50 286

>50 287

>40 288

289

32.733 290

0.470 291

0.370 292

0.270 293

1.080 294

295

3.820 296

3.250 297

0.025 298

299

300

301

302

>50 303

304

0.680 305

>50 306

2.900 307

5.360 308

2.750 309

310

8.780 311

312

0.025 313

1.630 314

0.047 315

0.267 316

0.690 317

1.170 318

0.037 319

0.195 320

1.020 321

0.030 322

0.180 323

0.360 324

1.175 325

0.340 326

2.750 327

0.610 328

0.220 329

8.870 330

0.120 331

0.085 332

0.050 333

334

0.140 335

0.490 336

0.420 337

0.165 338

0.035 339

0.093 340

0.080 341

0.085 342

0.090 343

0.600 344

0.250 345

0.140 346

0.330 347

0.300 348

0.455 349

>50 350

32.600 351

>50 352

0.880 353

18.500 354

0.380 355

0.140 356

>50 357

0.230 358

0.805 359

0.105 360

0.280 361

0.360 362

0.247 363

0.050 364

37.000 365

0.310 366

1.100 367

368

0.310 369

7.150 370

371

372

373

>50 374

3.580 375

6.360 376

6.070 377

2.550 378

379

0.705 380

0.420 381

>50 382

>50 383

>50 384

>50 385

8.867 386

387

>50 388

13.380 389

16.600 390

>50 391

>50 392

0.025 393

0.065 394

0.135 395

0.260 396

0.050 397

0.040 398

0.035 399

0.030 400

0.260 401

0.065 402

0.077 403

0.045 404

0.040 405

0.010 406

0.020 407

0.040 408

0.145 409

0.020 410

0.010 411

0.035 412

0.035 413

0.065 414

0.033 415

0.040 416

0.055 417

0.020 418

0.050 419

0.010 420

0.020 421

0.050 422

0.020 423

0.175 424

0.165 425

0.075 426

0.060 427

0.080 428

0.040 429

0.060 430

0.035 431

0.025 432

0.065 433

0.040 434

0.470 435

0.365 436

0.040 437

0.050 438

0.060 439

0.110 440

0.050 441

0.140 442

12.480 443

0.060 444

0.040 445

0.490 446

0.390 447

448

10.610 449

0.135 450

0.105 451

0.070 452

0.130 453

0.070 454

0.077 455

0.130 456

0.135 457

0.080 458

0.130 459

0.310 460

0.090 461

0.105 462

0.780 463

0.440 464

0.065 465

0.050 466

34.670 467

1.810 468

0.170 469

2.100 470

1.130 471

0.450 472

0.230 473

0.110 474

0.180 475

0.050 476

>50 477

0.130 478

0.420 479

0.110 480

0.180 481

21.240 482

0.240 483

0.100 484

0.070 485

0.130 486

0.540 487

0.380 488

0.030 489

0.180 490

0.090 491

0.070 492

0.030 493

0.090 494

>50

1. A method of treating fatty liver disease in a subject in needthereof, the method comprising administering to the subject a fatty acidsynthase inhibitor having a formula of: (a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R₂₁ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²² is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or alkyl; R³ is H or F; R¹¹ is H or—CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R ¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or (k)Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CN or halogen, R¹ isoptionally, substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l)Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₁-C₆ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 2. The method of claim 1,wherein the fatty liver disease is selected from non-alcoholic fattyliver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
 3. Themethod of claim 1 or 2, wherein the fatty liver disease is non-alcoholicsteatohepatitis (NASH).
 4. The method of any one of claims 1 to 3,wherein the fatty acid synthase inhibitor has a Formula (IX), (X),(XII), (XIV), (XV), or (XX).
 5. The method of any one of claims 1 to 4,wherein the fatty acid synthase inhibitor has a Formula (IX).
 6. Themethod of any one of claims 1 to 4, wherein the fatty acid synthaseinhibitor has a Formula (X).
 7. The method of any one of claims 1 to 4,wherein the fatty acid synthase inhibitor has a Formula (XII).
 8. Themethod of any one of claims 1 to 4, wherein the fatty acid synthaseinhibitor has a Formula (XIV).
 9. The method of any one of claims 1 to4, wherein the fatty acid synthase inhibitor has a Formula (XV).
 10. Themethod of any one of claims 1 to 4, wherein the fatty acid synthaseinhibitor has a Formula (XX).
 11. The method of any one of claims 1 to4, wherein the fatty acid synthase inhibitor is selected from:


12. The method of any one of claims 1 to 4, wherein the fatty acidsynthase inhibitor is selected from:


13. A method of treating non-alcoholic steatohepatitis (NASH), themethod comprising administering to a subject in need thereof a fattyacid synthase inhibitor having a formula of: (a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom, L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R₂₄ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(t)—(C₂-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1or 3; mis 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R₃₅₁ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or (k)Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l)Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R₂ is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ —O—(C₃-C₅ cycloalkyl), or —O-(4- to 6-memberedheterocycle), wherein R²⁴ is optionally substituted with one or morehydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 14. A method of treatingnon-alcoholic fatty liver disease (NAFLD), the method comprisingadministering to a subject in need thereof a fatty acid synthaseinhibitor having a formula of: (a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)², —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R₃ H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹,C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4-to 6-membered heterocycle, aryl or heteroaryl; or (k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₁-C₆ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 15. A method of treatingmetabolic syndrome, the method comprising administering to a subject inneed thereof a fatty acid synthase inhibitor having a formula of: (a)Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or (k)Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₁-C₆ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 16. A method of treating livercirrhosis, the method comprising administering to a subject in needthereof a fatty acid synthase inhibitor having a formula of: (a) Formula(IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₁-C₆ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —CN, halogen, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄ alkyl), or—C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom; s is 0, 1 or 2; each R⁶⁰¹ andR⁵⁰¹ is independently H or C₁-C₄ straight or branched alkyl; and whereintwo of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form a ringwherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, two R⁶⁰,two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R₃ H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹,C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4-to 6-membered heterocycle, aryl or heteroaryl; or (k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 17. A method of treating liverfibrosis, the method comprising administering to a subject in needthereof a fatty acid synthase inhibitor having a formula of: (a) Formula(IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —CN, halogen, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄ alkyl), or—C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom; s is 0, 1 or 2; each R⁶⁰¹ andR⁵⁰¹ is independently H or C₁-C₄ straight or branched alkyl; and whereintwo of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form a ringwherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, two R⁶⁰,two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²² is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or alkyl; R³ is H or F; R¹¹ is H or—CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)-(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or (k)Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₁-C₆ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 18. A method of treating livercancer, the method comprising administering to a subject in need thereofa fatty acid synthase inhibitor having a formula of: (a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), -0-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or (k)Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 19. A method of treating adisease or condition in which interleukin 1 beta (IL1β) levels areelevated, the method comprising administering to a subject in needthereof a fatty acid synthase inhibitor having a formula of: (a) Formula(IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N: L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, or NR⁵⁰; eachR⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl), —O—(C₁-C₄straight or branched alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, andthe C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 2or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branched alkyl,C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes anoxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; each R²⁶is independently —OH, —CN, halogen, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), alkyl)_(t)-O—(C₁-C₄straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄ alkyl), or—C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom; s is 0, 1 or 2; each R⁶⁰¹ andR⁵⁰¹ is independently H or C₁-C₄ straight or branched alkyl; and whereintwo of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form a ringwherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, two R⁶⁰,two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R₃ H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹,C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4-to 6-membered heterocycle, aryl or heteroaryl; or (k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₁-C₆ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 20. A method of treating adisease or condition in which t-helper (T_(h)) cell levels are elevated,the method comprising administering to a subject in need thereof a fattyacid synthase inhibitor having a formula of: (a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R₂ is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 2or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branched alkyl,C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes anoxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; each R²⁶is independently —OH, —CN, halogen, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄ alkyl), or—C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom; s is 0, 1 or 2; each R⁶⁰¹ andR⁵⁰¹ is independently H or C₁-C₄ straight or branched alkyl; and whereintwo of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form a ringwherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, two R⁶⁰,two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R₂₄ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or (k)Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 21. A method of treating adisease or condition in which regulatory t cells (T_(reg)) are reducedor suppressed, the method comprising administering to a subject in needthereof a fatty acid synthase inhibitor having a formula of: (a) Formula(IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R₂ is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom, L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 2or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branched alkyl,C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes anoxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; each R²⁶is independently —OH, —CN, halogen, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄ alkyl), or—C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom; s is 0, 1 or 2; each R⁶⁰¹ andR⁵⁰¹ is independently H or C₁-C₄ straight or branched alkyl; and whereintwo of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form a ringwherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, two R⁶⁰,two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ isC(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or (k)Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₁-C₆ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 22. A method of reversingestablished non-alcoholic steatohepatitis (NASH), the method comprisingadministering to a subject in need thereof a fatty acid synthaseinhibitor having a formula of: (a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R₂ is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 2or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branched alkyl,C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes anoxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; each R²⁶is independently OH, —CN, halogen, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄ alkyl), or—C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom; s is 0, 1 or 2; each R⁶⁰¹ andR⁵⁰¹ is independently H or C₁-C₄ straight or branched alkyl; and whereintwo of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to form a ringwherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may be two R²⁶, two R⁶⁰,two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R₃ H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹,C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4-to 6-membered heterocycle, aryl or heteroaryl; or (k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 23. A method of reducingfibrotic gene expression, the method comprising administering to asubject in need thereof a fatty acid synthase inhibitor having a formulaof: (a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH. —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C₁-C₄alkyl), wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴ and R²⁵ is independentlyH, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein: each t is independently 0 or 1;each u is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R₃ H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹,C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4-to 6-membered heterocycle, aryl or heteroaryl; or (k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₁-C₆ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 24. A method of treating skinfibrosis, the method comprising administering to a subject in needthereof a fatty acid synthase inhibitor having a formula of: (a) Formula(IX)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; or (b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹; or (c) Formula (VI-J)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or (d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl; or (e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C₁-C₄alkyl), wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴ and R²⁵ is independentlyH, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,—(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)-(C₃-C₅ cycloalkyl),—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ alkyl), wherein: each t is independently 0 or 1;each u is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; or (g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≥3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl; or (h)Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen; or (i) Formula(XVII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl; or (j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or snore halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R₃ H or F; R¹¹ is H or —CH₃; R²¹ is H,halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle;R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹,C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4-to 6-membered heterocycle, aryl or heteroaryl; or (k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to 6-memberedheterocycle; and R²² is H, halogen or C₁-C₂ alkyl; or (l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein: L-Ar is

Ar is

R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not H,—CN or halogen, R¹ is optionally substituted with one or more halogen;each R² is independently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F;R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen or C₁-C₂ alkyl; R²⁴ is —O—(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), —O—(C₃-C₅ cycloalkyl), or —O-(4- to6-membered heterocycle), wherein R²⁴ is optionally substituted with oneor more hydroxyl or halogen; and R²⁵ is H, halogen, C₁-C₄ alkyl or C₃-C₅cycloalkyl, wherein R²⁵ is optionally substituted with one or morehalogen; or (m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₁-C₆ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 25. The method of any one ofclaims 13 to 24, wherein the fatty acid synthase inhibitor has a Formula(IX), (X), (XII), (XIV), (XV), or (XX).
 26. The method of any one ofclaims 13 to 24, wherein the fatty acid synthase inhibitor has a Formula(IX).
 27. The method of any one of claims 13 to 24, wherein the fattyacid synthase inhibitor has a Formula (X).
 28. The method of any one ofclaims 13 to 24, wherein the fatty acid synthase inhibitor has a Formula(XII).
 29. The method of any one of claims 13 to 24, wherein the fattyacid synthase inhibitor has a Formula (XIV).
 30. The method of any oneof claims 13 to 24, wherein the fatty acid synthase inhibitor has aFormula (XV).
 31. The method of any one of claims 13 to 24, wherein thefatty acid synthase inhibitor has a Formula (XX).
 32. The method of anyone of claims 13 to 24, wherein the fatty acid synthase inhibitor isselected from:


33. The method of any one of claims 13 to 24, wherein the fatty acidsynthase inhibitor is selected from:


34. The method of claim 19, wherein the disease or condition is selectedfrom Familial Mediterranean fever (FMF), Pyogenic arthritis, pyodermagangrenosum, acne (PAPA), Cryopyrin-associated periodic syndromes(CAPS), Hyper IgD syndrome (HIDS), Adult and juvenile Still disease,Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS),Blau syndrome; Sweet syndrome, Deficiency in IL-1 receptor antagonist(DIRA), Recurrent idiopathic pericarditis, Macrophage activationsyndrome (MAS), Urticarial vasculitis, Antisynthetase syndrome,Relapsing chondritis, Behçet disease, Erdheim-Chester syndrome(histiocytosis), Synovitis, acne, pustulosis, hyperostosis, osteitis(SAPHO), Rheumatoid arthritis, Periodic fever, aphthous stomatitis,pharyngitis, adenitis syndrome (PFAPA), Urate crystal arthritis (gout),Type 2 diabetes, Smoldering multiple myeloma, Postmyocardial infarctionheart failure, Osteoarthritis, Transfusion-related acute lung injury,Ventilator-induced lung injury, Pulmonary fibrosis including Idiopathic,Chronic obstructive pulmonary disease and Asthma.
 35. The method ofclaim 20 or 21, wherein the disease or condition is selected fromPsoriasis, Rheumatoid arthritis, Multiple sclerosis, Ankylosingspondylitis, inflammatory bowel disease, asthma, tumorigenesis andtransplant rejection.
 36. The method of claim 20, wherein the elevatedt-helper cell is T_(h)1, T_(h)2, T_(h)9, or, T_(h)17.
 37. The method ofclaim 36, wherein the elevated t-helper cell is T₁₇.
 38. The method ofclaim 21, wherein T_(reg) cells are suppressed.
 39. The method of claim13, wherein treating the non-alcoholic steatohepatitis comprisesreversing at least one symptom of established non-alcoholicsteatohepatitis.
 40. The method of claim 13, wherein treating thenon-alcoholic steatohepatitis comprises preventing the progression of atleast one symptom of non-alcoholic steatohepatitis.
 41. The method ofclaim 39 or 40, wherein the symptom is selected from elevated levels ofAST; elevated levels of ALT; elevated levels of liver triglycerides;elevated levels of cholesterol; liver steatosis; liver inflammation;liver ballooning; liver fibrosis; and NAFLD activity score.